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RNA-binding proteins in vascular inflammation and atherosclerosis

  • Author Footnotes
    1 These authors contributed equally as first-authors.
    Marco Sachse
    Footnotes
    1 These authors contributed equally as first-authors.
    Affiliations
    Department of Cardiovascular Research, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Department of Cardiovascular Surgery, University Heart Center, University Hospital Hamburg Eppendorf, Hamburg, Germany
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  • Author Footnotes
    1 These authors contributed equally as first-authors.
    Simon Tual-Chalot
    Correspondence
    Corresponding author.
    Footnotes
    1 These authors contributed equally as first-authors.
    Affiliations
    Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
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  • Giorgia Ciliberti
    Affiliations
    Department of Cardiovascular Research, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    German Centre for Cardiovascular Research (Deutsches Zentrum für Herz-Kreislauf-Forschung, DZHK), Heidelberg/Mannheim Partner Site, Mannheim, Germany
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  • Michael Amponsah-Offeh
    Affiliations
    Department of Cardiovascular Research, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    German Centre for Cardiovascular Research (Deutsches Zentrum für Herz-Kreislauf-Forschung, DZHK), Heidelberg/Mannheim Partner Site, Mannheim, Germany
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  • Kimon Stamatelopoulos
    Affiliations
    Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece
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  • Aikaterini Gatsiou
    Affiliations
    Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
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  • Konstantinos Stellos
    Correspondence
    Corresponding author. Department of Cardiovascular Research, European Center for Angioscience (ECAS), Heidelberg University, Ludolf-Krehl-Straße 13-17, D-68167, Mannheim, Germany.
    Affiliations
    Department of Cardiovascular Research, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK

    German Centre for Cardiovascular Research (Deutsches Zentrum für Herz-Kreislauf-Forschung, DZHK), Heidelberg/Mannheim Partner Site, Mannheim, Germany

    Department of Cardiology, University Hospital Mannheim, Heidelberg University, Manheim, Germany
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  • Author Footnotes
    1 These authors contributed equally as first-authors.
Open AccessPublished:January 16, 2023DOI:https://doi.org/10.1016/j.atherosclerosis.2023.01.008

      Highlights

      • RNA-binding proteins (RBPs) are critical effectors of gene expression and emerge as key players of vascular inflammation and atherosclerosis.
      • RNA-binding protein function demonstrates a high degree of cell-specific effect in atherosclerosis.
      • Modulation of one RBP may alter the expression of several disease-related genes affecting a plethora of cellular functions.
      • Future studies are needed to report the organ- and cell-specific biological and clinical relevance of RBPs in atherosclerotic cardiovascular disease.

      Abstract

      Atherosclerotic cardiovascular disease (ASCVD) remains the major cause of premature death and disability worldwide, even when patients with an established manifestation of atherosclerotic heart disease are optimally treated according to the clinical guidelines. Apart from the epigenetic control of transcription of the genetic information to messenger RNAs (mRNAs), gene expression is tightly controlled at the post-transcriptional level before the initiation of translation. Although mRNAs are traditionally perceived as the messenger molecules that bring genetic information from the nuclear DNA to the cytoplasmic ribosomes for protein synthesis, emerging evidence suggests that processes controlling RNA metabolism, driven by RNA-binding proteins (RBPs), affect cellular function in health and disease. Over the recent years, vascular endothelial cell, smooth muscle cell and immune cell RBPs have emerged as key co- or post-transcriptional regulators of several genes related to vascular inflammation and atherosclerosis. In this review, we provide an overview of cell-specific function of RNA-binding proteins involved in all stages of ASCVD and how this knowledge may be used for the development of novel precision medicine therapeutics.

      Graphical abstract

      Keywords

      1. Introduction

      Atherosclerosis, a chronic, inflammatory, non-resolving vascular disease, is the most common manifestation of cardiovascular diseases. Despite the implementation of current clinical guideline-suggested medical therapy and prevention measures of major risk factors leading to atherosclerotic cardiovascular disease (ASCVD) such as hypercholesterolaemia, diabetes mellitus, smoking, hypertension and obesity, atherosclerosis remains the leading cause of mortality worldwide, accounting for millions of deaths mainly due to fatal myocardial infarction and stroke [,
      • Libby P.
      • Everett B.M.
      Novel antiatherosclerotic therapies.
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      • Bittencourt M.S.
      • Tokgözoğlu L.
      • Lewis E.F.
      Atherosclerosis.
      ].
      The development of atherosclerosis lesions is mostly initiated by sub-endothelial lipid accumulation in the arterial vascular wall. The turbulent blood flow at regions of curvature, bifurcation, and branching points of arterial vessels induces the upregulation of the expression of several proinflammatory genes in endothelial cells (ECs), the inner layer of the vessel bordering the luminal blood flow including adhesion molecules which trigger monocyte recruitment onto vascular wall. Recruited monocytes enter lesions, differentiate into macrophages and take up modified lipoproteins to develop into foam cells [
      • Libby P.
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      • Badimon L.
      • Hansson G.K.
      • Deanfield J.
      • Bittencourt M.S.
      • Tokgözoğlu L.
      • Lewis E.F.
      Atherosclerosis.
      ]. Smooth muscle cells (SMCs) undergo phenotypic switching from a contractile to a proliferative synthetic state, and migrate into the intima where they proliferate, produce extracellular matrix, and participate in the protective fibrous cap formation, promoting plaque stability [
      • Libby P.
      • Buring J.E.
      • Badimon L.
      • Hansson G.K.
      • Deanfield J.
      • Bittencourt M.S.
      • Tokgözoğlu L.
      • Lewis E.F.
      Atherosclerosis.
      ]. The accumulation of immune cells like monocytes, T-cells and natural killer cells in the lesion contributes to the chronic inflammation of the vascular wall. Subsequently, this pro-inflammatory environment triggers cell death of macrophages and smooth muscle cells to give rise to the necrotic, lipid-rich core of the atheroma [
      • Wolf D.
      • Ley K.
      Immunity and inflammation in atherosclerosis.
      ]. Eventually, the growing plaque will narrow the lumen of the vessels, and plaques with large lipid cores covered by a thinner fibrous cap become vulnerable and unstable. These plaques are prone to erosion or rupture, exposing their prothrombogenic collagenous core to circulating coagulation proteins, causing platelet adhesion and aggregation [
      • Libby P.
      • Pasterkamp G.
      • Crea F.
      • Jang I.K.
      Reassessing the mechanisms of acute coronary syndromes.
      ]. These events lead to thrombosis, an uncontrolled blockage of the vessel impairing the blood flow regulation, disrupting the oxygen and nutrient supply to the surrounding ischemic tissue that may lead to clinical complications such as myocardial infarction or stroke [
      • Libby P.
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      Reassessing the mechanisms of acute coronary syndromes.
      ,
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      Atherosclerosis: recent developments.
      ].
      ECs, SMCs and immune cells are key cell types in the development of atherosclerosis. Studies of cellular phenotypes in atherosclerosis have now provided considerable insights into the underlying mechanism leading to plaque development and clinical manifestation [
      • Libby P.
      • Buring J.E.
      • Badimon L.
      • Hansson G.K.
      • Deanfield J.
      • Bittencourt M.S.
      • Tokgözoğlu L.
      • Lewis E.F.
      Atherosclerosis.
      ,
      • Björkegren J.L.M.
      • Lusis A.J.
      Atherosclerosis: recent developments.
      ]. Emerging evidence has shown that RNA–binding proteins (RBPs) regulate molecular mechanisms controlling cellular function in atherosclerosis. Remarkably, recent bioinformatic analysis found that 165 RBPs were substantially changed in carotid atheroma compared to intact carotid tissue. More interestingly, 69 RBPs were differentially expressed between human carotid stable and unstable atherosclerotic plaques [
      • Tang Y.
      • Li Z.
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      YB1 dephosphorylation attenuates atherosclerosis by promoting CCL2 mRNA decay.
      ]. The modification of RBPs expression levels highlights the importance of RBPs in controlling different cellular phenotype changes that may determine not only the initiation of atherosclerotic plaque but also the progression toward plaque rupture.
      RBPs are proteins ubiquitously expressed across human tissues that recognize specific binding sequences and/or a secondary structures of RNA molecules controlling RNA metabolism either at the nuclear (transcription, splicing, capping, polyadenylation) or cytoplasmic (transport, localization, translation, degradation) level. RBPs can potentially bind to a wide variety of targets to exert their effects. In addition to binding to exons, introns, and untranslated regions (UTRs) of messenger RNA (mRNA), RBP can also bind to non-coding RNAs, such as long non-coding RNAs (lncRNAs), microRNA (miRNAs), circular RNAs (circRNAs), ribosomal RNA (rRNA), transfer RNA (tRNA), small nucleolar RNA (snoRNA), small interfering RNA (siRNA), telomerase RNA (TERC), and splicing small nucleolar RNA (snRNA) [
      • Treiber T.
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      A compendium of RNA-binding proteins that regulate MicroRNA biogenesis.
      ,
      • Yao Z.T.
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      • Liao L.
      • Chen K.S.
      • Li B.
      New insights into the interplay between long non-coding RNAs and RNA-binding proteins in cancer.
      ]. Besides the role of RBPs in regulation of RNA fate through direct binding, some RBPs inherit an enzymatic activity modifying the RNA canonical bases. There are currently over 170 modifications at RNA levels identified including A-to-I RNA editing, N6-methyladenosine or m5C 5-methylcytosine. These epitranscriptomic modifications influence every aspect of RNA metabolism to expand the range of RNA transcript functions and the protein-coding potential of the transcriptome [
      • Gatsiou A.
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      Adenosine-to-Inosine RNA editing in health and disease.
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      Dawn of epitranscriptomic medicine.
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      RNA epigenetics and cardiovascular diseases.
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      RNA modifications: importance in immune cell biology and related diseases.
      ].
      In this review, we will summarize the knowledge related to the role of RBPs in mRNA fate and accompanied tissue- and cell-specific functions in vascular inflammation and atherosclerosis. Due to space limitations, we will not refer to the role of RBPs that may indirectly control mRNA expression or translation in vascular inflammation and atherosclerosis by for instance chemically modifying RNA bases in mRNAs (e.g. like the adenosine deamination to inosine catalysed by the adenosine deaminase acting in RNA-1), or in small or long non-coding RNAs [
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      • Hedin U.
      • Zeiher A.M.
      • Dimmeler S.
      Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation.
      ,
      • Vlachogiannis N.I.
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      • Stamatelopoulos K.
      • Gatsiou A.
      • Sfikakis P.P.
      • Stellos K.
      Adenosine-to-inosine RNA editing contributes to type I interferon responses in systemic sclerosis.
      ,
      • Vlachogiannis N.I.
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      • Tektonidou M.G.
      • Gallo A.
      • Sfikakis P.P.
      • Stellos K.
      Increased adenosine-to-inosine RNA editing in rheumatoid arthritis.
      ,
      • van den Homberg D.A.L.
      • van der Kwast R.V.C.T.
      • Quax P.H.A.
      • Nossent A.Y.
      N-6-Methyladenosine in vasoactive microRNAs during hypoxia; A novel role for METTL4.
      ,
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      • Zhang L.
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      • Quax P.H.A.
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      Cold-inducible RNA-binding protein but not its antisense lncRNA is a direct negative regulator of angiogenesis in vitro and in vivo via regulation of the 14q32 angiomiRs-microRNA-329-3p and microRNA-495-3p.
      ,
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      Adenosine-to-Inosine editing of vasoactive MicroRNAs alters their targetome and function in ischemia.
      ,
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      • Parma L.
      • Peters H.A.B.
      • Quax P.H.A.
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      Adenosine-to-Inosine editing of MicroRNA-487b alters target gene selection after ischemia and promotes neovascularization.
      ]. State-of-the-art reviews have recently addressed the role of epitranscriptomic modifications in atherosclerotic cardiovascular disease (ASCVD) [
      • Gatsiou A.
      • Vlachogiannis N.
      • Lunella F.F.
      • Sachse M.
      • Stellos K.
      Adenosine-to-Inosine RNA editing in health and disease.
      ,
      • Dorn L.E.
      • Tual-Chalot S.
      • Stellos K.
      • Accornero F.
      RNA epigenetics and cardiovascular diseases.
      ,
      • Choy M.
      • Xue R.
      • Wu Y.
      • Fan W.
      • Dong Y.
      • Liu C.
      Role of N6-methyladenosine modification in cardiac remodeling.
      ,
      • Woudenberg T.
      • Kruyt N.D.
      • Quax P.H.A.
      • Nossent A.Y.
      Change of heart: the epitranscriptome of small non-coding RNAs in heart failure.
      ,
      • Kumari R.
      • Ranjan P.
      • Suleiman Z.G.
      • Goswami S.K.
      • Li J.
      • Prasad R.
      • Verma S.K.
      mRNA modifications in cardiovascular biology and disease: with a focus on m6A modification.
      ]. The role of RBPs in non-coding RNA processing (e.g. microRNA and circular RNA biogenesis and targeting) or non-coding RNA function have been recently covered in previous review manuscripts [
      • Ding Y.
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      The combined regulation of long non-coding RNA and RNA-binding proteins in atherosclerosis.
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      MicroRNA regulation of atherosclerosis.
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      Epigenetic modification in coronary atherosclerosis: JACC review topic of the week.
      ].

      2. Role of RNA-binding proteins in RNA metabolism

      RNA processing is a critical component of gene expression and regulation and requires great coordination among all the factors involved in this control. RBPs are involved in the regulation of target genes by recognizing RNA, mainly with specific sequences to dictate the fate of mRNA [
      • Hentze M.W.
      • Castello A.
      • Schwarzl T.
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      A brave new world of RNA-binding proteins.
      ]. It is predicted that the human genome encodes around 1500 proteins with at least one RNA-binding domain, representing 7.5% of all protein-coding genes in humans, underlying the complexity of post-transcriptional regulation [
      • Gerstberger S.
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      A census of human RNA-binding proteins.
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      • Burge C.B.
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      A large-scale binding and functional map of human RNA-binding proteins.
      ]. RBPs are evolutionarily deeply conserved across species, suggesting that RNA metabolism is one of the most conserved cellular processes [
      • Gerstberger S.
      • Hafner M.
      • Tuschl T.
      A census of human RNA-binding proteins.
      ,
      • Gerstberger S.
      • Hafner M.
      • Ascano M.
      • Tuschl T.
      Evolutionary conservation and expression of human RNA-binding proteins and their role in human genetic disease.
      ]. RBPs bound to the same type of RNA across species and exhibits usually similar function in similar tissue to display similar pathologies [
      • Gerstberger S.
      • Hafner M.
      • Tuschl T.
      A census of human RNA-binding proteins.
      ]. Interestingly, the RBP-RNA interaction network remains also preserved, with a significantly higher conservation of the binding sites occurring in the 3′ UTR regions, suggesting that post-transcriptional regulatory processes like stability control, localization and degradation of transcripts are significantly more conserved across species [
      • Ramakrishnan A.
      • Janga S.C.
      Human protein-RNA interaction network is highly stable across mammals.
      ]. The basic properties and pleiotropic functions of RBPs have been expertly discussed in recent reviews, and we will briefly summarize their main mechanisms of action here [
      • Treiber T.
      • Treiber N.
      • Plessmann U.
      • Harlander S.
      • Daiß J.L.
      • Eichner N.
      • Lehmann G.
      • Schall K.
      • Urlaub H.
      • Meister G.
      A compendium of RNA-binding proteins that regulate MicroRNA biogenesis.
      ,
      • Yao Z.T.
      • Yang Y.M.
      • Sun M.M.
      • He Y.
      • Liao L.
      • Chen K.S.
      • Li B.
      New insights into the interplay between long non-coding RNAs and RNA-binding proteins in cancer.
      ,
      • Hentze M.W.
      • Castello A.
      • Schwarzl T.
      • Preiss T.
      A brave new world of RNA-binding proteins.
      ,
      • Gerstberger S.
      • Hafner M.
      • Tuschl T.
      A census of human RNA-binding proteins.
      ].
      RBP play a fundamental role in pre-mRNA processing (Fig. 1A). First, RBPs facilitate the addition of a 5′cap, a structure crucial for regulating splicing, degradation, and stability of transcripts. RBPs also function in the regulation of splicing, the selection of specific exons over others. RBPs interact with the spliceosome, a large RNA-protein complex, to catalyse the removal of introns. RBP binding motifs are near splicing sites interfering with the splicing factors resulting in alternative spliced variants. RBPs may also cause intron retention or alternative stop codons by influencing these intronic splicing sites. Additionally, RBPs are involved in alternative polyadenylation at the 3′ UTR of the transcript, resulting in different mRNA, and protein isoforms expanding the proteome complexity [
      • Yao Z.T.
      • Yang Y.M.
      • Sun M.M.
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      New insights into the interplay between long non-coding RNAs and RNA-binding proteins in cancer.
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      The combined regulation of long non-coding RNA and RNA-binding proteins in atherosclerosis.
      ,
      • Hentze M.W.
      • Castello A.
      • Schwarzl T.
      • Preiss T.
      A brave new world of RNA-binding proteins.
      ].
      Fig. 1
      Fig. 1Schematic drawing of RNA-binding proteins regulating RNA fate.
      RNA binding protein (RBP) regulates post-transcriptionally RNA metabolism at the nucleus and at the cytoplasm level. (A) RBPs regulate pre-mRNA processing by ensuring a proper 5′ cap (1), interfering with splicing and alternative splicing (2) causing intron retention or a new stop codon (3) and regulating alternative polyadenylation (4). (B) Then, RBP regulate mRNA cellular localization by either nuclear retention (5), nuclear-cytoplasm shuttling (6) or storing mRNA in stress granular upon cellular stress (7). (C) RBPs increase mRNA stability ensuring proper mRNA processing (8) or initiate degradation by recruiting nucleases (9). Competitive binding interactions between miRNAs and RBPs for a specific target region (10a). Synergistic interactions between miRNAs and RBPs to share a specific target (10b). RBPs expression levels can also be directly regulated by miRNAs, while RBPs can modulate miRNA biogenesis, function and degradation (10c). (D) Finally, RBPs balance translation of the target mRNA by either initiating translation (11), controlling the rate and efficiency of translation (12) or by terminating the translational process (13).
      The subcellular localization of an mRNA is essential in the further regulation of its stability and translation. RBPs dictate mRNA localization by interfering with the transport of target mRNA out of the nucleus (Fig. 1B). Upon certain stimuli like hypoxia, lipid accumulation, viral infection or cellular stress, mRNA can either be retained in the nucleus, transported to the cytoplasm, or transported to stress granular within the nucleus to be stored or released at a later stage [
      • Yao Z.T.
      • Yang Y.M.
      • Sun M.M.
      • He Y.
      • Liao L.
      • Chen K.S.
      • Li B.
      New insights into the interplay between long non-coding RNAs and RNA-binding proteins in cancer.
      ,
      • Ding Y.
      • Yin R.
      • Zhang S.
      • Xiao Q.
      • Zhao H.
      • Pan X.
      • Zhu X.
      The combined regulation of long non-coding RNA and RNA-binding proteins in atherosclerosis.
      ,
      • Hentze M.W.
      • Castello A.
      • Schwarzl T.
      • Preiss T.
      A brave new world of RNA-binding proteins.
      ].
      RBPs also orchestrate mRNA stability and degradation to regulate the abundance and lifespan of cellular mRNAs (Fig. 1C). RBP binding to mRNA may increase its stability and inhibit interaction with the degradation machinery to ensure proper translation processing. Alternatively, RBPs may promote the mRNA nucleases-regulating degradation. Since multiple RNA binding protein motifs are located close to miRNA binding motifs, RBPs and miRNAs affect mRNA stability, splicing and translation efficiency through either competition or synergy. RBPs expression levels can also be directly regulated by miRNAs, while RBPs can modulate miRNA biogenesis, function, and degradation, highlighting the complexity of the miRNAs and RBPs interplay [
      • Treiber T.
      • Treiber N.
      • Plessmann U.
      • Harlander S.
      • Daiß J.L.
      • Eichner N.
      • Lehmann G.
      • Schall K.
      • Urlaub H.
      • Meister G.
      A compendium of RNA-binding proteins that regulate MicroRNA biogenesis.
      ,
      • Ding Y.
      • Yin R.
      • Zhang S.
      • Xiao Q.
      • Zhao H.
      • Pan X.
      • Zhu X.
      The combined regulation of long non-coding RNA and RNA-binding proteins in atherosclerosis.
      ,
      • Gerstberger S.
      • Hafner M.
      • Tuschl T.
      A census of human RNA-binding proteins.
      ,
      • Gerstberger S.
      • Hafner M.
      • Ascano M.
      • Tuschl T.
      Evolutionary conservation and expression of human RNA-binding proteins and their role in human genetic disease.
      ,
      • Jiang P.
      • Coller H.
      Functional interactions between microRNAs and RNA binding proteins.
      ].
      Finally, RBPs regulate the recruitment of ribosomal subunits initiating the translation of target mRNA (Fig. 1D). Translational rate and efficiency are regulated by RBP, altering the protein expression of mRNAs. RBPs regulate not only the initiation of translation, but also its termination [
      • Ding Y.
      • Yin R.
      • Zhang S.
      • Xiao Q.
      • Zhao H.
      • Pan X.
      • Zhu X.
      The combined regulation of long non-coding RNA and RNA-binding proteins in atherosclerosis.
      ,
      • Gerstberger S.
      • Hafner M.
      • Tuschl T.
      A census of human RNA-binding proteins.
      ].
      Accumulating evidence demonstrates that modulation of RBPs expression in clinical and preclinical models is critically involved in promoting or preventing the development and progression of atherosclerotic plaque (Table 1). These studies suggest a fundamental role for RBPs in every stage of atherosclerotic disease. We will now discuss RBPs' role in the initiation, progression, and rupture of atherosclerotic plaque by focusing on the regulation of these processes, including endothelial dysfunction, lipid accumulation, vascular remodeling, immune cell regulation and inflammation. We will also discuss a potential role for RBPs in therapeutic interventions and the possible use of RBPs as biomarkers for atherosclerotic disease and acute ischemic events.
      Table 1Evidence of the role of RNA-binding proteins in pre-clinical model of atherosclerosis.
      Athero-genicityModelTargets/Genes regulatedEffect on target/gene expressionEffect of tissue-specific RBP in atherosclerotic diseaseRef.
      Human antigen R (HuR)
      ProEC-specific HuR knockout in ApoE−/− mouseIL-6, IL-8, IL-1β, CCL2, CXCL1, CXCL12, VCAM, ICAM, SELE, CXCR2, SELP, CCR1, IL-6RIncreases expression.EC HuR increases atherosclerotic surface area and monocyte recruitment onto vascular wall.[
      • Fu X.
      • Zhai S.
      • Yuan J.
      Endothelial HuR deletion reduces the expression of proatherogenic molecules and attenuates atherosclerosis.
      ]
      AntiSMC-specific HuR knockout mouseRGS2, RGS4, RGS5Increases stability.VSMC HuR reduces systolic blood pressure and contractility of VSMC[
      • Liu S.
      • Jiang X.
      • Lu H.
      • Xing M.
      • Qiao Y.
      • Zhang C.
      • Zhang W.
      HuR (human antigen R) regulates the contraction of vascular smooth muscle and maintains blood pressure.
      ]
      AntiSMC-specific HuR knockout mouseAMPKα1, AMPKα2Increases stability and translation.VSMC HuR reduces plaque area, macrophage content and plaque vulnerability.[
      • Liu S.
      • Jiang X.
      • Cui X.
      • Wang J.
      • Liu S.
      • Li H.
      • Yang J.
      • Zhang C.
      • Zhang W.
      Smooth muscle-specific HuR knockout induces defective autophagy and atherosclerosis.
      ]
      Quaking (QKI)
      ProTransplanted bone marrow from mice with reduced levels of QKI into LDLR−/− mouseSplicing: ADD3, PARP2, M6PR, BICD2, Expression: NR1H3 (LXRα), ABCG1, PPARG (PPARγ)Regulates pre-mRNA splicing and increases expression.QKI increases monocyte adhesion onto ECs, increases migration, differentiation to macrophages and foam cell formation.[
      • de Bruin R.G.
      • Shiue L.
      • Prins J.
      • de Boer H.C.
      • Singh A.
      • Fagg W.S.
      • van Gils J.M.
      • Duijs J.M.
      • Katzman S.
      • Kraaijeveld A.O.
      • Böhringer S.
      • Leung W.Y.
      • Kielbasa S.M.
      • Donahue J.P.
      • van der Zande P.H.
      • Sijbom R.
      • van Alem C.M.
      • Bot I.
      • van Kooten C.
      • Jukema J.W.
      • Van Esch H.
      • Rabelink T.J.
      • Kazan H.
      • Biessen E.A.
      • Ares Jr., M.
      • van Zonneveld A.J.
      • van der Veer E.P.
      Quaking promotes monocyte differentiation into pro-atherogenic macrophages by controlling pre-mRNA splicing and gene expression.
      ]
      SUB1 homolog (SUB1)
      ProMyeloid‐specific SUB1 knockout in ApoE−/− mouseIrf1Increases expression.Myeloid SUB1 increases atherosclerotic lesion area, reduced collagen and decrease anti-inflammatory M2 polarized macrophage content.[
      • Huang R.
      • Hu Z.
      • Chen X.
      • Cao Y.
      • Li H.
      • Zhang H.
      • Li Y.
      • Liang L.
      • Feng Y.
      • Wang Y.
      • Su W.
      • Kong Z.
      • Melgiri N.D.
      • Jiang L.
      • Li X.
      • Du J.
      • Chen Y.
      The transcription factor SUB1 is a master regulator of the macrophage TLR response in atherosclerosis.
      ]
      Tristetraprolin (TTP)
      AntiTTP knockout mouseS1008A, CTSS, VCAM-1, ICAM-1, SPP1, MIP-1α, TNF-α, CD68, NOX2Decreases stability (NOX2) and expressionTTP reduces endothelial dysfunction and macrophage infiltration into the intima.[
      • Bollmann F.
      • Wu Z.
      • Oelze M.
      • Siuda D.
      • Xia N.
      • Henke J.
      • Daiber A.
      • Li H.
      • Stumpo D.J.
      • Blackshear P.J.
      • Kleinert H.
      • Pautz A.
      Endothelial dysfunction in tristetraprolin-deficient mice is not caused by enhanced tumor necrosis factor-α expression.
      ]
      AntiTTP knockout mouse in ApoE−/− mouseCCL3Reduces mRNA stability and expression.TTP reduces atherosclerotic plaque area.[
      • Kang J.G.
      • Amar M.J.
      • Remaley A.T.
      • Kwon J.
      • Blackshear P.J.
      • Wang P.Y.
      • Hwang P.M.
      Zinc finger protein tristetraprolin interacts with CCL3 mRNA and regulates tissue inflammation.
      ]
      VSMC, vascular smooth muscle cell; BMDM, bone marrow derived macrophages; EC, endothelial cell; CASMC, coronary artery smooth muscle cell; iPS, induced pluripotent stem cell; AMPKα1, adenosine 5′-monophosphate-activated protein kinase α1; AMPKα2, adenosine 5′-monophosphate-activated protein kinase α2; IL-6, Interleukin-6; IL-8, Interleukin-8, IL-1β, Interleukin-1 beta; CCL2, CC-chemokine ligand 2; CXCL1, C-X-C Motif Chemokine Ligand 1; CXCL12, C-X-C Motif Chemokine Ligand 12; VCAM1, vascular cell adhesion molecule 1; ICAM1, Intercellular adhesion molecule 1; SELE, Selectin E; CXCR2, C-X-C Motif Chemokine Receptor 2; SELP, Selectin P; CCR1, C–C chemokine receptor type 1; IL-6R, Interleukin 6 receptor; RGS2, Regulator Of G Protein Signaling 2; RGS4, Regulator Of G Protein Signaling 4; RGS5, Regulator Of G Protein Signaling 5; ADD3, Adducin 3; PARP2, Poly(ADP-Ribose) Polymerase 2; M6PR, Mannose-6-Phosphate Receptor; BICD2, BICD Cargo Adaptor 2; NR1H3, Nuclear Receptor Subfamily 1 Group H Member 3; ABCG1, ATP Binding Cassette Subfamily G Member 1; PPARG, Peroxisome Proliferator Activated Receptor Gamma; Irf1, Interferon Regulatory Factor 1; CCL3, CC-chemokine ligand 3; S1008A, S100 Calcium Binding Protein A8; CTSS, Cathepsin S; SPP1, Secreted Phosphoprotein 1; MIP-1α, Macrophage Inflammatory Proteins 1 alpha; TNF-α, Tumor Necrosis Factor alpha; CD68, Cluster of Differentiation 68; NOX2, NADPH oxidase 2.

      3. RNA-binding proteins and the regulation of endothelial function

      ECs form a single monolayer that lines all blood vessels and regulates exchanges between the bloodstream and the surrounding tissues through their junctions. The shear stress observed in areas of curvature and branching increased endothelial permeability and led to the elevated entry of low-density lipoprotein (LDL) into the wall via widened intercellular junctions [
      • Zhang X.
      • Sessa W.C.
      • Fernández-Hernando C.
      Endothelial transcytosis of lipoproteins in atherosclerosis.
      ,
      • Weinberg P.D.
      Haemodynamic wall shear stress, endothelial permeability and atherosclerosis-A triad of controversy.
      ]. The subsequent lipoprotein oxidation and continued shear stress enhance EC dysfunction causing an upregulation of adhesion molecules expression, a process tightly regulated by RBPs.
      For instance, Human antigen R (HuR), also named ELAV-like RNA binding protein 1 (ELAVL1), is a stress-sensitive RBP ubiquitously expressed in tissues whose increased expression in response to oscillatory shear stress led to endothelial activation and further monocyte recruitment [
      • Rhee W.J.
      • Ni C.W.
      • Zheng Z.
      • Chang K.
      • Jo H.
      • Bao G.
      HuR regulates the expression of stress-sensitive genes and mediates inflammatory response in human umbilical vein endothelial cells.
      ,
      • Bibli S.I.
      • Hu J.
      • Sigala F.
      • Wittig I.
      • Heidler J.
      • Zukunft S.
      • Tsilimigras D.I.
      • Randriamboavonjy V.
      • Wittig J.
      • Kojonazarov B.
      • Schürmann C.
      • Siragusa M.
      • Siuda D.
      • Luck B.
      • Abdel Malik R.
      • Filis K.A.
      • Zografos G.
      • Chen C.
      • Wang D.W.
      • Pfeilschifter J.
      • Brandes R.P.
      • Szabo C.
      • Papapetropoulos A.
      • Fleming I.
      Cystathionine γ lyase sulfhydrates the RNA binding protein human antigen R to preserve endothelial cell function and delay atherogenesis.
      ]. HuR regulates the stability and translation of its target mRNAs by recognizing mainly 3′ UTRs of mRNAs with AU-rich element (ARE)- and U-rich element (URE) [
      • Pullmann Jr., R.
      • Juhaszova M.
      • López de Silanes I.
      • Kawai T.
      • Mazan-Mamczarz K.
      • Halushka M.K.
      • Gorospe M.
      Enhanced proliferation of cultured human vascular smooth muscle cells linked to increased function of RNA-binding protein HuR.
      ,
      • Ray M.
      • Gabunia K.
      • Vrakas C.N.
      • Herman A.B.
      • Kako F.
      • Kelemen S.E.
      • Grisanti L.A.
      • Autieri M.V.
      Genetic deletion of IL-19 (Interleukin-19) exacerbates atherogenesis in Il19-/-×Ldlr-/- double knockout mice by dysregulation of mRNA stability protein HuR (human antigen R).
      ]. Overexpression of VCAM-1, ICAM-1 and SELE has been consistently observed in atherosclerotic lesion sites [
      • Nakashima Y.
      • Raines E.W.
      • Plump A.S.
      • Breslow J.L.
      • Ross R.
      Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse.
      ,
      • Hwang S.J.
      • Ballantyne C.M.
      • Sharrett A.R.
      • Smith L.C.
      • Davis C.E.
      • Gotto Jr., A.M.
      • Boerwinkle E.
      Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk in Communities (ARIC) study.
      ]. These adhesion molecules contain AU-rich elements in their 3′ UTRs, facilitating HuR binding to these sites [
      • Rhee W.J.
      • Ni C.W.
      • Zheng Z.
      • Chang K.
      • Jo H.
      • Bao G.
      HuR regulates the expression of stress-sensitive genes and mediates inflammatory response in human umbilical vein endothelial cells.
      ,
      • Cheng H.S.
      • Sivachandran N.
      • Lau A.
      • Boudreau E.
      • Zhao J.L.
      • Baltimore D.
      • Delgado-Olguin P.
      • Cybulsky M.I.
      • Fish J.E.
      MicroRNA-146 represses endothelial activation by inhibiting pro-inflammatory pathways.
      ]. Therefore, HuR knockdown decreased ICAM-1 and VCAM-1 expression and the subsequent monocyte adhesion [
      • Rhee W.J.
      • Ni C.W.
      • Zheng Z.
      • Chang K.
      • Jo H.
      • Bao G.
      HuR regulates the expression of stress-sensitive genes and mediates inflammatory response in human umbilical vein endothelial cells.
      ,
      • Cheng H.S.
      • Sivachandran N.
      • Lau A.
      • Boudreau E.
      • Zhao J.L.
      • Baltimore D.
      • Delgado-Olguin P.
      • Cybulsky M.I.
      • Fish J.E.
      MicroRNA-146 represses endothelial activation by inhibiting pro-inflammatory pathways.
      ]. Conversely, HuR was shown to maintain low levels of SELE expression to minimize monocyte adhesion at sites of low or disturbed flow [
      • Bibli S.I.
      • Hu J.
      • Sigala F.
      • Wittig I.
      • Heidler J.
      • Zukunft S.
      • Tsilimigras D.I.
      • Randriamboavonjy V.
      • Wittig J.
      • Kojonazarov B.
      • Schürmann C.
      • Siragusa M.
      • Siuda D.
      • Luck B.
      • Abdel Malik R.
      • Filis K.A.
      • Zografos G.
      • Chen C.
      • Wang D.W.
      • Pfeilschifter J.
      • Brandes R.P.
      • Szabo C.
      • Papapetropoulos A.
      • Fleming I.
      Cystathionine γ lyase sulfhydrates the RNA binding protein human antigen R to preserve endothelial cell function and delay atherogenesis.
      ]. In addition, endothelial HuR deletion was associated with reduced leukocyte recruitment to the aortic endothelium, and plaque size in ApoE−/− mouse model of atherosclerosis (Fig. 2) [
      • Fu X.
      • Zhai S.
      • Yuan J.
      Endothelial HuR deletion reduces the expression of proatherogenic molecules and attenuates atherosclerosis.
      ]. Other RBPs may regulate adhesion molecules expression. For instance, AUF1, the first ARE-binding RBP identified, was known primarily to promote the decay of target mRNAs, although the stabilization of some other transcripts has also been reported [
      • Zhang W.
      • Wagner B.J.
      • Ehrenman K.
      • Schaefer A.W.
      • DeMaria C.T.
      • Crater D.
      • DeHaven K.
      • Long L.
      • Brewer G.
      Purification, characterization, and cDNA cloning of an AU-rich element RNA-binding protein, AUF1.
      ,
      • White E.J.
      • Matsangos A.E.
      • Wilson G.M.
      AUF1 regulation of coding and noncoding RNA.
      ]. In human coronary artery cells, activation of AUF1 increases VCAM-1 mRNA stability and may participate in further monocyte infiltration [
      • Huang C.Y.
      • Shih C.M.
      • Tsao N.W.
      • Chen Y.H.
      • Li C.Y.
      • Chang Y.J.
      • Chang N.C.
      • Ou K.L.
      • Lin C.Y.
      • Lin Y.W.
      • Nien C.H.
      • Lin F.Y.
      GroEL1, from Chlamydia pneumoniae, induces vascular adhesion molecule 1 expression by p37(AUF1) in endothelial cells and hypercholesterolemic rabbit.
      ]. In contrast, the presence of Zinc finger protein tristetraprolin (TTP), a RBP known to destabilize inflammatory cytokine mRNAs via binding to AU-rich elements, reduces VCAM-1 and ICAM-1 expression in the murine aorta and is essential to maintain endothelial homeostasis [
      • Bollmann F.
      • Wu Z.
      • Oelze M.
      • Siuda D.
      • Xia N.
      • Henke J.
      • Daiber A.
      • Li H.
      • Stumpo D.J.
      • Blackshear P.J.
      • Kleinert H.
      • Pautz A.
      Endothelial dysfunction in tristetraprolin-deficient mice is not caused by enhanced tumor necrosis factor-α expression.
      ,
      • Blackshear P.J.
      Tristetraprolin and other CCCH tandem zinc-finger proteins in the regulation of mRNA turnover.
      ].
      Fig. 2
      Fig. 2RNA-binding protein HuR contribution to atherosclerosis.
      HuR regulates numerous processes in atherosclerotic disease progression. Vascular endothelial HuR expression increased in plaque lead to activation of endothelial cells through the regulation of genes involved in migration, inflammation and adhesion. Macrophage HuR expression is also increased in human plaque. Upon inflammatory response, HuR increases cytokine and adhesion molecules production, leading to monocyte recruitment. HuR contributes also to the T cells recruitment and proliferation. In contrast, HuR also has atheroprotective properties. As lipids accumulate in the vasculature, HuR increases lipid transport and cholesterol efflux in the macrophages. Smooth muscle cell HuR expression decreased in murine plaque model is essential to maintain the contraction and regulate the blood pressure, decrease the proliferation, autophagy and inflammation.
      Loss of vascular integrity is another hallmark of endothelial activation occurring in atherosclerosis [
      • Libby P.
      • Buring J.E.
      • Badimon L.
      • Hansson G.K.
      • Deanfield J.
      • Bittencourt M.S.
      • Tokgözoğlu L.
      • Lewis E.F.
      Atherosclerosis.
      ,
      • Björkegren J.L.M.
      • Lusis A.J.
      Atherosclerosis: recent developments.
      ]. The K homology-type QUAKING (QKI) is an RBP from the conserved STAR (signal transduction and activation of RNA) family protein that plays an essential role during embryonic and postnatal development by regulating blood vessel development [
      • Li Z.
      • Takakura N.
      • Oike Y.
      • Imanaka T.
      • Araki K.
      • Suda T.
      • Kaname T.
      • Kondo T.
      • Abe K.
      • Yamamura K.
      Defective smooth muscle development in qkI-deficient mice.
      ]. Laminar shear stress induces QKI expression in quiescent ECs is required for the maintenance of endothelial barrier function and the control of vascular leakage in homeostatic condition by increasing the expression of VE-cadherin and β-catenin [
      • de Bruin R.G.
      • van der Veer E.P.
      • Prins J.
      • Lee D.H.
      • Dane M.J.
      • Zhang H.
      • Roeten M.K.
      • Bijkerk R.
      • de Boer H.C.
      • Rabelink T.J.
      • van Zonneveld A.J.
      • van Gils J.M.
      The RNA-binding protein quaking maintains endothelial barrier function and affects VE-cadherin and β-catenin protein expression.
      ]. However, this regulation seems to be impaired in disease states. QKI-7 expression, an isoform of QKI, is increased in induced pluripotent stem (iPS) cell-derived ECs exposed to hyperglycemia, and in human iPS-ECs from diabetic patients [
      • Yang C.
      • Eleftheriadou M.
      • Kelaini S.
      • Morrison T.
      • González M.V.
      • Caines R.
      • Edwards N.
      • Yacoub A.
      • Edgar K.
      • Moez A.
      • Ivetic A.
      • Zampetaki A.
      • Zeng L.
      • Wilkinson F.L.
      • Lois N.
      • Stitt A.W.
      • Grieve D.J.
      • Margariti A.
      Targeting QKI-7 in vivo restores endothelial cell function in diabetes.
      ]. QKI-7 upregulation enhances mRNA degradation of VE-cadherin and subsequently increases vascular permeability and may contribute to endothelial dysfunction [
      • Yang C.
      • Eleftheriadou M.
      • Kelaini S.
      • Morrison T.
      • González M.V.
      • Caines R.
      • Edwards N.
      • Yacoub A.
      • Edgar K.
      • Moez A.
      • Ivetic A.
      • Zampetaki A.
      • Zeng L.
      • Wilkinson F.L.
      • Lois N.
      • Stitt A.W.
      • Grieve D.J.
      • Margariti A.
      Targeting QKI-7 in vivo restores endothelial cell function in diabetes.
      ]. Furthermore, QKI-7 upregulation contributes to enhanced monocyte adhesion and may lead to the development of atherosclerosis in diabetes (Fig. 3) [
      • Yang C.
      • Eleftheriadou M.
      • Kelaini S.
      • Morrison T.
      • González M.V.
      • Caines R.
      • Edwards N.
      • Yacoub A.
      • Edgar K.
      • Moez A.
      • Ivetic A.
      • Zampetaki A.
      • Zeng L.
      • Wilkinson F.L.
      • Lois N.
      • Stitt A.W.
      • Grieve D.J.
      • Margariti A.
      Targeting QKI-7 in vivo restores endothelial cell function in diabetes.
      ].
      Fig. 3
      Fig. 3RNA-binding protein QKI contribution to atherosclerosis.
      QKI expression is increased in endothelial cells, macrophages and smooth muscle cells from plaque model of atherosclerosis. In endothelial cells QKI regulates vascular permeability, promotes angiogenesis and regulates adhesion molecule expression. As lipid accumulates in atherosclerotic lesions, QKI increases lipid uptake by monocytes, thereby increasing foam cell formation. In smooth muscle cells, QKI contributes to phenotypic switching and the production of extracellular matrix products.

      4. RNA-binding proteins regulate lipoprotein entry, modification, and metabolism

      Low-density lipoprotein accumulation during atherogenesis induces aggregation of lipoprotein particles, endothelial damage, leukocyte recruitment, foam cell formation, apoptosis, and inflammation [
      • Libby P.
      • Buring J.E.
      • Badimon L.
      • Hansson G.K.
      • Deanfield J.
      • Bittencourt M.S.
      • Tokgözoğlu L.
      • Lewis E.F.
      Atherosclerosis.
      ,
      • Borén J.
      • Chapman M.J.
      • Krauss R.M.
      • Packard C.J.
      • Bentzon J.F.
      • Binder C.J.
      • Daemen M.J.
      • Demer L.L.
      • Hegele R.A.
      • Nicholls S.J.
      • Nordestgaard B.G.
      • Watts G.F.
      • Bruckert E.
      • Fazio S.
      • Ference B.A.
      • Graham I.
      • Horton J.D.
      • Landmesser U.
      • Laufs U.
      • Masana L.
      • Pasterkamp G.
      • Raal F.J.
      • Ray K.K.
      • Schunkert H.
      • Taskinen M.R.
      • van de Sluis B.
      • Wiklund O.
      • Tokgozoglu L.
      • Catapano A.L.
      • Ginsberg H.N.
      Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel.
      ]. RBPs can also affect metabolic homeostasis by affecting mRNAs involved in the regulation of lipid metabolism (Table 2). Lowering lipid metabolism is currently the first line of treatment in atherosclerosis pharmacological management [
      • Libby P.
      • Everett B.M.
      Novel antiatherosclerotic therapies.
      ]. The importance of cholesterol efflux in reducing macrophage foam cell formation could also be a complementary approach in reducing atherosclerosis burden [
      • Tall A.R.
      • Yvan-Charvet L.
      • Terasaka N.
      • Pagler T.
      • Wang N.
      HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis.
      ,
      • Khera A.V.
      • Cuchel M.
      • de la Llera-Moya M.
      • Rodrigues A.
      • Burke M.F.
      • Jafri K.
      • French B.C.
      • Phillips J.A.
      • Mucksavage M.L.
      • Wilensky R.L.
      • Mohler E.R.
      • Rothblat G.H.
      • Rader D.J.
      Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis.
      ]. The cholesterol efflux pathways regulated by ATP-binding cassette transporters like ABCA1 and ABCG1 protect cells from free cholesterol and oxysterol-induced toxicity [
      • Westerterp M.
      • Murphy A.J.
      • Wang M.
      • Pagler T.A.
      • Vengrenyuk Y.
      • Kappus M.S.
      • Gorman D.J.
      • Nagareddy P.R.
      • Zhu X.
      • Abramowicz S.
      • Parks J.S.
      • Welch C.
      • Fisher E.A.
      • Wang N.
      • Yvan-Charvet L.
      • Tall A.R.
      Deficiency of ATP-binding cassette transporters A1 and G1 in macrophages increases inflammation and accelerates atherosclerosis in mice.
      ,
      • Rosenson R.S.
      • Brewer Jr., H.B.
      • Davidson W.S.
      • Fayad Z.A.
      • Fuster V.
      • Goldstein J.
      • Hellerstein M.
      • Jiang X.C.
      • Phillips M.C.
      • Rader D.J.
      • Remaley A.T.
      • Rothblat G.H.
      • Tall A.R.
      • Yvan-Charvet L.
      Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport.
      ]. Interestingly, HuR expression and nuclear localization are regulated by cholesterol contents [
      • Ramírez C.M.
      • Lin C.S.
      • Abdelmohsen K.
      • Goedeke L.
      • Yoon J.H.
      • Madrigal-Matute J.
      • Martin-Ventura J.L.
      • Vo D.T.
      • Uren P.J.
      • Penalva L.O.
      • Gorospe M.
      • Fernández-Hernando C.
      RNA binding protein HuR regulates the expression of ABCA1.
      ]. HuR binds to ABCA1 and ABCG1 3’ UTR to enhance their protein translation and increase cellular cholesterol efflux in human macrophages (Fig. 2) [
      • Ramírez C.M.
      • Lin C.S.
      • Abdelmohsen K.
      • Goedeke L.
      • Yoon J.H.
      • Madrigal-Matute J.
      • Martin-Ventura J.L.
      • Vo D.T.
      • Uren P.J.
      • Penalva L.O.
      • Gorospe M.
      • Fernández-Hernando C.
      RNA binding protein HuR regulates the expression of ABCA1.
      ]. Conversely, a decreased QKI expression in human monocytes significantly increases cholesterol efflux genes ABCA1 and ABCG1 [
      • de Bruin R.G.
      • Shiue L.
      • Prins J.
      • de Boer H.C.
      • Singh A.
      • Fagg W.S.
      • van Gils J.M.
      • Duijs J.M.
      • Katzman S.
      • Kraaijeveld A.O.
      • Böhringer S.
      • Leung W.Y.
      • Kielbasa S.M.
      • Donahue J.P.
      • van der Zande P.H.
      • Sijbom R.
      • van Alem C.M.
      • Bot I.
      • van Kooten C.
      • Jukema J.W.
      • Van Esch H.
      • Rabelink T.J.
      • Kazan H.
      • Biessen E.A.
      • Ares Jr., M.
      • van Zonneveld A.J.
      • van der Veer E.P.
      Quaking promotes monocyte differentiation into pro-atherogenic macrophages by controlling pre-mRNA splicing and gene expression.
      ]. Considering that QKI mRNA is 4-fold enriched in macrophages derived from advanced as compared with early atherosclerotic lesions, the maintenance of low QKI expression seems to be essential to enhance cholesterol efflux and protect against plaque progression (Fig. 3) [
      • de Bruin R.G.
      • Shiue L.
      • Prins J.
      • de Boer H.C.
      • Singh A.
      • Fagg W.S.
      • van Gils J.M.
      • Duijs J.M.
      • Katzman S.
      • Kraaijeveld A.O.
      • Böhringer S.
      • Leung W.Y.
      • Kielbasa S.M.
      • Donahue J.P.
      • van der Zande P.H.
      • Sijbom R.
      • van Alem C.M.
      • Bot I.
      • van Kooten C.
      • Jukema J.W.
      • Van Esch H.
      • Rabelink T.J.
      • Kazan H.
      • Biessen E.A.
      • Ares Jr., M.
      • van Zonneveld A.J.
      • van der Veer E.P.
      Quaking promotes monocyte differentiation into pro-atherogenic macrophages by controlling pre-mRNA splicing and gene expression.
      ].
      Table 2Role of RNA-binding proteins in Lipid metabolism.
      Tissue/cell specificityTargetEffect on target expressionEffect of tissue-specific RBP in metabolism and atherosclerosisRef.
      Cold-inducible RNA-binding protein (CIRP)
      Murine lung tissueiNOS, 4-HNEIncreases expressionCIRP increases lipid peroxidation and oxidative stress in acute lung injury in a murine sepsis model[
      • Khan M.M.
      • Yang W.L.
      • Brenner M.
      • Bolognese A.C.
      • Wang P.
      Cold-inducible RNA-binding protein (CIRP) causes sepsis-associated acute lung injury via induction of endoplasmic reticulum stress.
      ]
      Human antigen R (HuR)
      Human hepatic cells and monocytesABCA1Increases expression independent of stabilityMyeloid HuR increases cholesterol efflux to ApoAI[
      • Ramírez C.M.
      • Lin C.S.
      • Abdelmohsen K.
      • Goedeke L.
      • Yoon J.H.
      • Madrigal-Matute J.
      • Martin-Ventura J.L.
      • Vo D.T.
      • Uren P.J.
      • Penalva L.O.
      • Gorospe M.
      • Fernández-Hernando C.
      RNA binding protein HuR regulates the expression of ABCA1.
      ]
      Murine liver tissue, murine hepatoma cellApoBAlternative splicingHepatic HuR increases ATP synthesis and lipid transport[
      • Zhang Z.
      • Zong C.
      • Jiang M.
      • Hu H.
      • Cheng X.
      • Ni J.
      • Yi X.
      • Jiang B.
      • Tian F.
      • Chang M.W.
      • Su W.
      • Zhu L.
      • Li J.
      • Xiang X.
      • Miao C.
      • Gorospe M.
      • de Cabo R.
      • Dou Y.
      • Ju Z.
      • Yang J.
      • Jiang C.
      • Yang Z.
      • Wang W.
      Hepatic HuR modulates lipid homeostasis in response to high-fat diet.
      ]
      Cycs, Ndufb6, UqcrbBIncreases expression
      Murine liver tissue, Human hepatoma cellsLDLRIncreases stability and expressionHepatic HuR reduces triglyceride content in serum and liver[
      • Singh A.B.
      • Dong B.
      • Kraemer F.B.
      • Xu Y.
      • Zhang Y.
      • Liu J.
      Farnesoid X receptor activation by obeticholic acid elevates liver low-density lipoprotein receptor expression by mRNA stabilization and reduces Plasma low-density lipoprotein cholesterol in mice.
      ]
      Murine adipocytes and adipose tissueATGLIncreases stability, expression and translationAdipose HuR reduces obesity through regulation of lipolysis and insulin resistance[
      • Li J.
      • Gong L.
      • Liu S.
      • Zhang Y.
      • Zhang C.
      • Tian M.
      • Lu H.
      • Bu P.
      • Yang J.
      • Ouyang C.
      • Jiang X.
      • Wu J.
      • Zhang Y.
      • Min Q.
      • Zhang C.
      • Zhang W.
      Adipose HuR protects against diet-induced obesity and insulin resistance.
      ]
      Human and mouse preadipocyteInsig1Increases stability and expressionAdipose HuR reduces adipogenesis through regulation of glucose intolerance and insulin resistance[
      • Siang D.T.C.
      • Lim Y.C.
      • Kyaw A.M.M.
      • Win K.N.
      • Chia S.Y.
      • Degirmenci U.
      • Hu X.
      • Tan B.C.
      • Walet A.C.E.
      • Sun L.
      • Xu D.
      The RNA-binding protein HuR is a negative regulator in adipogenesis.
      ]
      Fragile-X mental retardation autosomal 1 (FXR1)
      Murine liver cellsApoMReduces expressionHepatic FXR1 promotes atherogenesis[
      • Yang L.
      • Li T.
      LncRNA TUG1 regulates ApoM to promote atherosclerosis progression through miR-92a/FXR1 axis.
      ]
      Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1)
      Human hepatic cellsHMGCRAlternative splicingHepatic HNRNPA1 increases LDL-uptake and cellular ApoB expression[
      • Yu C.Y.
      • Theusch E.
      • Lo K.
      • Mangravite L.M.
      • Naidoo D.
      • Kutilova M.
      • Medina M.W.
      HNRNPA1 regulates HMGCR alternative splicing and modulates cellular cholesterol metabolism.
      ]
      Murine satellite cellsPGC1a, CD36, CPT1bIncreases translation and expressionSatellite cell HNRNPA1 positively regulates lipid metabolism[
      • Gui W.
      • Zhu W.F.
      • Zhu Y.
      • Tang S.
      • Zheng F.
      • Yin X.
      • Lin X.
      • Li H.
      LncRNAH19 improves insulin resistance in skeletal muscle by regulating heterogeneous nuclear ribonucleoprotein A1.
      ]
      Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2)
      Murine fat tissueUcp1Suppresses translationAdipose IGF2BP2 modulates nutrient and energy metabolism by reducing uncoupled oxygen consumption, glucose tolerance and insulin sensitivity[
      • Dai N.
      • Zhao L.
      • Wrighting D.
      • Krämer D.
      • Majithia A.
      • Wang Y.
      • Cracan V.
      • Borges-Rivera D.
      • Mootha V.K.
      • Nahrendorf M.
      • Thorburn D.R.
      • Minichiello L.
      • Altshuler D.
      • Avruch J.
      IGF2BP2/IMP2-Deficient mice resist obesity through enhanced translation of Ucp1 mRNA and Other mRNAs encoding mitochondrial proteins.
      ]
      Murine hepatocytesCPT-1A, PPARΑIncreases stability and translationHepatic IGF2BP2 increases lipid oxidation.[
      • Regué L.
      • Minichiello L.
      • Avruch J.
      • Dai N.
      Liver-specific deletion of IGF2 mRNA binding protein-2/IMP2 reduces hepatic fatty acid oxidation and increases hepatic triglyceride accumulation.
      ]
      Murine adipocytesHMGA1, IGF2, PPARα, ADIPOR1, ELOVL6, SCDIncreases translation and expressionAdipose IGF2BP2 modulates adipocyte differentiation and lipid metabolism[
      • Zhang X.
      • Xue C.
      • Lin J.
      • Ferguson J.F.
      • Weiner A.
      • Liu W.
      • Han Y.
      • Hinkle C.
      • Li W.
      • Jiang H.
      • Gosai S.
      • Hachet M.
      • Garcia B.A.
      • Gregory B.D.
      • Soccio R.E.
      • Hogenesch J.B.
      • Seale P.
      • Li M.
      • Reilly M.P.
      Interrogation of nonconserved human adipose lincRNAs identifies a regulatory role of linc-ADAL in adipocyte metabolism.
      ]
      Quaking (QKI)
      Murine monocytesCD36, LDLR, ABCG1, NR1H3, PPARGIncreases expressionMyeloid QKI impairs foam cell formation in monocytes and macrophages[
      • de Bruin R.G.
      • Shiue L.
      • Prins J.
      • de Boer H.C.
      • Singh A.
      • Fagg W.S.
      • van Gils J.M.
      • Duijs J.M.
      • Katzman S.
      • Kraaijeveld A.O.
      • Böhringer S.
      • Leung W.Y.
      • Kielbasa S.M.
      • Donahue J.P.
      • van der Zande P.H.
      • Sijbom R.
      • van Alem C.M.
      • Bot I.
      • van Kooten C.
      • Jukema J.W.
      • Van Esch H.
      • Rabelink T.J.
      • Kazan H.
      • Biessen E.A.
      • Ares Jr., M.
      • van Zonneveld A.J.
      • van der Veer E.P.
      Quaking promotes monocyte differentiation into pro-atherogenic macrophages by controlling pre-mRNA splicing and gene expression.
      ]
      Human monocytesSRAReduces expressionMyeloid QKI reduces lipid uptake in monocytes to macrophage differentiation[
      • Wang S.
      • Zan J.
      • Wu M.
      • Zhao W.
      • Li Z.
      • Pan Y.
      • Sun Z.
      • Zhu J.
      miR-29a promotes scavenger receptor A expression by targeting QKI (quaking) during monocyte-macrophage differentiation.
      ]
      Src-Associated substrate in Mitosis of 68 kDa (Sam68)
      Inguinal and epididymal white adipose tissueUcp1, Prdm16, Dio2, Cidea, Elovl3, Cidec, Cpt1bReduces expressionAdipose Sam68 suppresses fat tissue browning[
      • Zhou J.
      • Cheng M.
      • Boriboun C.
      • Ardehali M.M.
      • Jiang C.
      • Liu Q.
      • Han S.
      • Goukassian D.A.
      • Tang Y.L.
      • Zhao T.C.
      • Zhao M.
      • Cai L.
      • Richard S.
      • Kishore R.
      • Qin G.
      Inhibition of Sam68 triggers adipose tissue browning.
      ]
      Murine Preadipocyte and fat tissueRps6kb1Alternative splicingAdipose Sam68 modulates adipogenesis[
      • Song J.
      • Richard S.
      Sam68 regulates S6K1 alternative splicing during adipogenesis.
      ]
      Murine PreadipocytemTORAlternative splicingAdipose Sam68 induces adipogenesis and reduces energy expenditure in mice[
      • Huot M.É.
      • Vogel G.
      • Zabarauskas A.
      • Ngo C.T.
      • Coulombe-Huntington J.
      • Majewski J.
      • Richard S.
      The Sam68 STAR RNA-binding protein regulates mTOR alternative splicing during adipogenesis.
      ]
      SUB1 homolog (SUB1)
      Murine BMDMAbcg1, Abca1Reduces expressionMyeloid Sub1 upregulates cholesterol accumulation in macrophages[
      • Huang R.
      • Hu Z.
      • Chen X.
      • Cao Y.
      • Li H.
      • Zhang H.
      • Li Y.
      • Liang L.
      • Feng Y.
      • Wang Y.
      • Su W.
      • Kong Z.
      • Melgiri N.D.
      • Jiang L.
      • Li X.
      • Du J.
      • Chen Y.
      The transcription factor SUB1 is a master regulator of the macrophage TLR response in atherosclerosis.
      ]
      Olr1, Irf1Increases expression
      Tristetraprolin (TTP)
      Murine primary hepatocytesFGF21Reduces stability and expressionHepatic TTP reduces insulin sensitivity and brown fat activation[
      • Sawicki K.T.
      • Chang H.C.
      • Shapiro J.S.
      • Bayeva M.
      • De Jesus A.
      • Finck B.N.
      • Wertheim J.A.
      • Blackshear P.J.
      • Ardehali H.
      Hepatic tristetraprolin promotes insulin resistance through RNA destabilization of FGF21.
      ]
      BMDM, bone marrow derived macrophage; iNOS, inducible nitric oxide synthase; 4-HNE, 4-hydroxy-2-nonenal; ABCA1, ATP Binding Cassette Subfamily A Member 1; ApoB, Apolipoprotein B; Cycs, Cytochrome C, Somatic; Ndufb6, NADH: Ubiquinone Oxidoreductase Subunit B; Uqcrb, Ubiquinol-Cytochrome C Reductase Binding Protein; LDLR, Low Density Lipoprotein Receptor; ATGL, Adipose triglyceride lipase; Insig1, Insulin Induced Gene 1; ApoM, Apolipoprotein M; HMGCR, -Hydroxy-3-Methylglutaryl-CoA Reductase; PGC1a, PPARG Coactivator 1 Alpha; CD36, cluster of differentiation 36; CPT1b, Carnitine Palmitoyltransferase 1B; CPT-1A, Carnitine Palmitoyltransferase 1A; PPARα, Peroxisome Proliferator Activated Receptor Alpha; Ucp1, Uncoupling Protein 1; HMGA1, High Mobility Group AT-Hook 1; IGF2, Insulin Like Growth Factor 2; ADIPOR1, Adiponectin Receptor 1; ELOVL6, ELOVL Fatty Acid Elongase 6; SCD, Stearoyl-CoA Desaturase; ABCG1, ATP Binding Cassette Subfamily G Member 1; NR1H3, Nuclear Receptor Subfamily 1 Group H Member 3; PPARG, Peroxisome Proliferator Activated Receptor Gamma; SRA, scavenger receptor A; Prdm16, PR/SET Domain 16; Dio2, Iodothyronine Deiodinase 2; Cidea, Cell Death Inducing DFFA Like Effector A; Elovl3, ELOVL Fatty Acid Elongase 3; Cidec, Cell Death Inducing DFFA Like Effector C;Rps6kb1, Rps6kb1; mTOR, Mechanistic Target Of Rapamycin Kinase; Olr1, Oxidized Low Density Lipoprotein Receptor 1; Irf1, Interferon Regulatory Factor 1; Fgf21, Fibroblast Growth Factor 21.
      Apolipoprotein B, the main apolipoprotein composed of LDL, triglyceride (TG)-rich lipoproteins, remnants of chylomicrons and very low-density lipoproteins (VLDL), is a relevant biomarker in the progression of atherosclerosis [
      • Behbodikhah J.
      • Ahmed S.
      • Elyasi A.
      • Kasselman L.J.
      • De Leon J.
      • Glass A.D.
      • Reiss A.B.
      Apolipoprotein B and cardiovascular disease: biomarker and potential therapeutic target.
      ]. Trapping of Apolipoprotein B within the arterial wall initiates and drives the atherosclerotic process [
      • Behbodikhah J.
      • Ahmed S.
      • Elyasi A.
      • Kasselman L.J.
      • De Leon J.
      • Glass A.D.
      • Reiss A.B.
      Apolipoprotein B and cardiovascular disease: biomarker and potential therapeutic target.
      ]. Hepatic HuR increases Apolipoprotein B production through splicing events [
      • Zhang Z.
      • Zong C.
      • Jiang M.
      • Hu H.
      • Cheng X.
      • Ni J.
      • Yi X.
      • Jiang B.
      • Tian F.
      • Chang M.W.
      • Su W.
      • Zhu L.
      • Li J.
      • Xiang X.
      • Miao C.
      • Gorospe M.
      • de Cabo R.
      • Dou Y.
      • Ju Z.
      • Yang J.
      • Jiang C.
      • Yang Z.
      • Wang W.
      Hepatic HuR modulates lipid homeostasis in response to high-fat diet.
      ]. Therefore, the absence of hepatic HuR in high-fat diet mice reduced the levels of serum lipids and may protect arteries from atherosclerosis by helping to maintain lipid homeostasis [
      • Zhang Z.
      • Zong C.
      • Jiang M.
      • Hu H.
      • Cheng X.
      • Ni J.
      • Yi X.
      • Jiang B.
      • Tian F.
      • Chang M.W.
      • Su W.
      • Zhu L.
      • Li J.
      • Xiang X.
      • Miao C.
      • Gorospe M.
      • de Cabo R.
      • Dou Y.
      • Ju Z.
      • Yang J.
      • Jiang C.
      • Yang Z.
      • Wang W.
      Hepatic HuR modulates lipid homeostasis in response to high-fat diet.
      ]. In contrast, Apolipoprotein M, a component of high-density lipoprotein (HDL) particles, exhibits various anti-atherosclerotic functions such as protection against oxidation and regulation of cholesterol efflux [
      • Wolfrum C.
      • Poy M.N.
      • Stoffel M.
      Apolipoprotein M is required for prebeta-HDL formation and cholesterol efflux to HDL and protects against atherosclerosis.
      ]. Fragile X Mental Retardation Syndrome-Related Protein 1 (FXR1), a destabilizing RBPs like TTP and AUF1, plays a critical role in post-transcriptional regulation by altering the transcript stability of genes involved in immunity, development, and cancer [
      • Herman A.B.
      • Vrakas C.N.
      • Ray M.
      • Kelemen S.E.
      • Sweredoski M.J.
      • Moradian A.
      • Haines D.S.
      • Autieri M.V.
      FXR1 is an IL-19-responsive RNA-binding protein that destabilizes pro-inflammatory transcripts in vascular smooth muscle cells.
      ,
      • Qian J.
      • Hassanein M.
      • Hoeksema M.D.
      • Harris B.K.
      • Zou Y.
      • Chen H.
      • Lu P.
      • Eisenberg R.
      • Wang J.
      • Espinosa A.
      • Ji X.
      • Harris F.T.
      • Rahman S.M.
      • Massion P.P.
      The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers.
      ,
      • Le Tonqueze O.
      • Kollu S.
      • Lee S.
      • Al-Salah M.
      • Truesdell S.S.
      • Vasudevan S.
      Regulation of monocyte induced cell migration by the RNA binding protein, FXR1.
      ,
      • Mientjes E.J.
      • Willemsen R.
      • Kirkpatrick L.L.
      • Nieuwenhuizen I.M.
      • Hoogeveen-Westerveld M.
      • Verweij M.
      • Reis S.
      • Bardoni B.
      • Hoogeveen A.T.
      • Oostra B.A.
      • Nelson D.L.
      Fxr1 knockout mice show a striated muscle phenotype: implications for Fxr1p function in vivo.
      ]. FXR1 may also contribute to atherosclerosis progression by decreasing ApoM mRNA expression in murine liver cells [
      • Yang L.
      • Li T.
      LncRNA TUG1 regulates ApoM to promote atherosclerosis progression through miR-92a/FXR1 axis.
      ].
      LDL Receptor (LDLR) is a crucial receptor for cholesterol homeostasis and a major determinant of the circulating levels of low-density lipoprotein-associated cholesterol [
      • Libby P.
      • Buring J.E.
      • Badimon L.
      • Hansson G.K.
      • Deanfield J.
      • Bittencourt M.S.
      • Tokgözoğlu L.
      • Lewis E.F.
      Atherosclerosis.
      ,
      • Goldstein J.L.
      • Brown M.S.
      The LDL receptor.
      ]. Interestingly, AU-rich elements (AREs) are present on the 3′UTR of LDLR mRNA, allowing HuR binding to ensure transcript stability, increased expression, and enhanced removal of circulating LDL-C [
      • Singh A.B.
      • Dong B.
      • Kraemer F.B.
      • Xu Y.
      • Zhang Y.
      • Liu J.
      Farnesoid X receptor activation by obeticholic acid elevates liver low-density lipoprotein receptor expression by mRNA stabilization and reduces Plasma low-density lipoprotein cholesterol in mice.
      ]. QKI absence in murine monocytes reduced LDLR mRNA expression as well as CD36, a receptor involved in lipid uptake [
      • Wang S.
      • Zan J.
      • Wu M.
      • Zhao W.
      • Li Z.
      • Pan Y.
      • Sun Z.
      • Zhu J.
      miR-29a promotes scavenger receptor A expression by targeting QKI (quaking) during monocyte-macrophage differentiation.
      ]. Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), an mRNA splicing regulator, increased LDL-C uptake and enhanced apolipoprotein B expression by modulating the expression level of an alternatively spliced transcript of HMGCR, a rate-limiting enzyme of the cholesterol biosynthesis pathway [
      • Yu C.Y.
      • Theusch E.
      • Lo K.
      • Mangravite L.M.
      • Naidoo D.
      • Kutilova M.
      • Medina M.W.
      HNRNPA1 regulates HMGCR alternative splicing and modulates cellular cholesterol metabolism.
      ].
      Lipid oxidation products also have a prominent role in the development of atherosclerosis, nursing the acute inflammatory response [
      • Stocker R.
      • Keaney Jr., J.F.
      Role of oxidative modifications in atherosclerosis.
      ]. RNA-binding protein IGF2 mRNA binding protein-2 (IMP2) may play an important role in the control of cell metabolism [
      • Degrauwe N.
      • Suvà M.L.
      • Janiszewska M.
      • Riggi N.
      • Stamenkovic I.
      IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer.
      ]. IMP2−/− mice have a metabolic phenotype extending their lifespan and rendering them resistant to diet-induced obesity and type-II diabetes, possibly through its regulation of mitochondrial function [
      • Janiszewska M.
      • Suvà M.L.
      • Riggi N.
      • Houtkooper R.H.
      • Auwerx J.
      • Clément-Schatlo V.
      • Radovanovic I.
      • Rheinbay E.
      • Provero P.
      • Stamenkovic I.
      Imp2 controls oxidative phosphorylation and is crucial for preserving glioblastoma cancer stem cells.
      ,
      • Dai N.
      • Zhao L.
      • Wrighting D.
      • Krämer D.
      • Majithia A.
      • Wang Y.
      • Cracan V.
      • Borges-Rivera D.
      • Mootha V.K.
      • Nahrendorf M.
      • Thorburn D.R.
      • Minichiello L.
      • Altshuler D.
      • Avruch J.
      IGF2BP2/IMP2-Deficient mice resist obesity through enhanced translation of Ucp1 mRNA and Other mRNAs encoding mitochondrial proteins.
      ]. IMP2 stabilizes PPARα and CPT-1A mRNAs, two critical regulators of hepatic fatty acid oxidation, resulting in reduced mitochondrial fatty acid oxidation [
      • Dai N.
      • Zhao L.
      • Wrighting D.
      • Krämer D.
      • Majithia A.
      • Wang Y.
      • Cracan V.
      • Borges-Rivera D.
      • Mootha V.K.
      • Nahrendorf M.
      • Thorburn D.R.
      • Minichiello L.
      • Altshuler D.
      • Avruch J.
      IGF2BP2/IMP2-Deficient mice resist obesity through enhanced translation of Ucp1 mRNA and Other mRNAs encoding mitochondrial proteins.
      ,
      • Regué L.
      • Minichiello L.
      • Avruch J.
      • Dai N.
      Liver-specific deletion of IGF2 mRNA binding protein-2/IMP2 reduces hepatic fatty acid oxidation and increases hepatic triglyceride accumulation.
      ]. Interestingly, single-nucleotide polymorphisms identified in the IMP2 gene correlate with elevated risk of type 2 diabetes [
      • Christiansen J.
      • Kolte A.M.
      • Hansen Tv
      • Nielsen F.C.
      IGF2 mRNA-binding protein 2: biological function and putative role in type 2 diabetes.
      ]. In contrast, HuR directly targets genes known to regulate adipogenesis, and its absence in adipose tissues of high-fat diet mice led to obesity, impaired lipolysis and insulin resistance [
      • Li J.
      • Gong L.
      • Liu S.
      • Zhang Y.
      • Zhang C.
      • Tian M.
      • Lu H.
      • Bu P.
      • Yang J.
      • Ouyang C.
      • Jiang X.
      • Wu J.
      • Zhang Y.
      • Min Q.
      • Zhang C.
      • Zhang W.
      Adipose HuR protects against diet-induced obesity and insulin resistance.
      ,
      • Siang D.T.C.
      • Lim Y.C.
      • Kyaw A.M.M.
      • Win K.N.
      • Chia S.Y.
      • Degirmenci U.
      • Hu X.
      • Tan B.C.
      • Walet A.C.E.
      • Sun L.
      • Xu D.
      The RNA-binding protein HuR is a negative regulator in adipogenesis.
      ].

      5. RNA-binding proteins in the regulation of smooth muscle cell phenotype

      SMCs play a fundamental role in plaque stability during atherosclerosis. Upon lipids or cytokines stimulation, SMCs switch from a contractile to a proliferative synthetic state, generating extracellular matrix proteins for forming the fibrous cap, retaining LDL leading to foam cell formation, and participating in monocyte recruitment through cytokine secretion [
      • Basatemur G.L.
      • Jørgensen H.F.
      • Clarke M.C.H.
      • Bennett M.R.
      • Mallat Z.
      Vascular smooth muscle cells in atherosclerosis.
      ]. SMCs plasticity, a pivotal process leading to phenotypical switches, is orchestrated by multiple RBPs during atherosclerosis progression (Table 3).
      Table 3Role of RNA-binding proteins in smooth muscle cell function in atherosclerosis.
      Tissue/Cells studiedTargetEffect on target expressionEffect of tissue-specific RBP in smooth muscle cell regulationRef.
      DEAD box protein 5 (DDX-5)
      Murine VSMCsCyclin D1, PCNADecreases expressionSMC DDX-5 reduces proliferation, migration and vascular remodeling[
      • Fan Y.
      • Chen Y.
      • Zhang J.
      • Yang F.
      • Hu Y.
      • Zhang L.
      • Zeng C.
      • Xu Q.
      Protective role of RNA helicase DEAD-box protein 5 in smooth muscle cell proliferation and vascular remodeling.
      ]
      P27, GATA-6Increases expression
      Human antigen R (HuR)
      Human aortic SMCsSAT1, CDK2Increases expressionHuR promotes SMC proliferation[
      • Pullmann Jr., R.
      • Juhaszova M.
      • López de Silanes I.
      • Kawai T.
      • Mazan-Mamczarz K.
      • Halushka M.K.
      • Gorospe M.
      Enhanced proliferation of cultured human vascular smooth muscle cells linked to increased function of RNA-binding protein HuR.
      ]
      Rat aortic SMCssGCβ1Increases stability and expressionSMC HuR enhances relaxation of rat aorta[
      • Martín-Garrido A.
      • González-Ramos M.
      • Griera M.
      • Guijarro B.
      • Cannata-Andia J.
      • Rodriguez-Puyol D.
      • Rodriguez-Puyol M.
      • Saura M.
      H2O2 regulation of vascular function through sGC mRNA stabilization by HuR.
      ]
      Human aortic VSMCsCRP, TNF-α, TLR4Regulation of expressionSMC HuR increases inflammation and induces VSMC proliferation[
      • Liu Liang
      The anti-inflammatory effect of miR-16 through targeting C- reactive protein is regulated by HuR in vascular smooth muscle cells.
      ]
      Human aortic SMCsTLR4Increases stability and expressionSMC HuR is increased upon balloon-injury in rat aorta and aggravates TLR4 expression under LPS-stimulation[
      • Lin F.Y.
      • Chen Y.H.
      • Lin Y.W.
      • Tsai J.S.
      • Chen J.W.
      • Wang H.J.
      • Chen Y.L.
      • Li C.Y.
      • Lin S.J.
      The role of human antigen R, an RNA-binding protein, in mediating the stabilization of toll-like receptor 4 mRNA induced by endotoxin: a novel mechanism involved in vascular inflammation.
      ]
      Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1)
      Murine VSMCsIQGAP1Reduces stability and expressionSMC hnRNPA1 reduces proliferation in neointima formation in wire-injured carotid arteries[
      • Zhang L.
      • Chen Q.
      • An W.
      • Yang F.
      • Maguire E.M.
      • Chen D.
      • Zhang C.
      • Wen G.
      • Yang M.
      • Dai B.
      • Luong L.A.
      • Zhu J.
      • Xu Q.
      • Xiao Q.
      Novel pathological role of hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1) in vascular smooth muscle cell function and neointima hyperplasia.
      ]
      Murine ESC-derived VSMCsActa2, Tagin, SRF, MEF2c, MyocdIncreases expressionSMC hnRNPA1 increases VSMC differentiation from stem cells[
      • Huang Y.
      • Lin L.
      • Yu X.
      • Wen G.
      • Pu X.
      • Zhao H.
      • Fang C.
      • Zhu J.
      • Ye S.
      • Zhang L.
      • Xiao Q.
      Functional involvements of heterogeneous nuclear ribonucleoprotein A1 in smooth muscle differentiation from stem cells in vitro and in vivo.
      ]
      Heterogeneous Nuclear Ribonucleoprotein A2/B1 (hnRNPA2B1)
      Murine ESC-derived SMCsSMαA, SM-MHC, SRF, Cbx3, MYOCD.Increases expressionSMC hnRNPA2/B1 induces SMC differentiation from stem cells and arterial development[
      • Wang G.
      • Xiao Q.
      • Luo Z.
      • Ye S.
      • Xu Q.
      Functional impact of heterogeneous nuclear ribonucleoprotein A2/B1 in smooth muscle differentiation from stem cells and embryonic arteriogenesis.
      ]
      VSMCshnRNPA2/B1Reduces expressionSMC hnRNPA2/B1 promotes atherosclerotic VSMC proliferation[
      • Zhang R.Y.
      • Wu C.M.
      • Hu X.M.
      • Lin X.M.
      • Hua Y.N.
      • Chen J.J.
      • Ding L.
      • He X.
      • Yang B.
      • Ping B.H.
      • Zheng L.
      • Wang Q.
      LncRNA AC105942.1 downregulates hnRNPA2/B1 to attenuate vascular smooth muscle cells proliferation.
      ]
      Muscleblind Like Splicing Regulator 1 (MBNL1)
      Human aortic VSMCsAbi1Alternative splicingSMC MBNL1 induces macrophage-like phenotype differentiation of VSMC[
      • Li Y.
      • Guo X.
      • Xue G.
      • Wang H.
      • Wang Y.
      • Wang W.
      • Yang S.
      • Ni Q.
      • Chen J.
      • Lv L.
      • Zhao Y.
      • Ye M.
      • Zhang L.
      RNA Splicing of the Abi1 Gene by MBNL1 contributes to macrophage-like phenotype modulation of vascular smooth muscle cell during atherogenesis.
      ]
      Polypyrimidine tract binding proteins ½ (PTBP1/2)
      Rat pulmonary artery SMCsDock7, Atp2b4, Dst, Pkm, Actn1, Tpm1, Itga7Alternative splicingSMC PTBP1/PTBP2 regulates alternative splicing during SMC de-differentiation[
      • Llorian M.
      • Gooding C.
      • Bellora N.
      • Hallegger M.
      • Buckroyd A.
      • Wang X.
      • Rajgor D.
      • Kayikci M.
      • Feltham J.
      • Ule J.
      • Eyras E.
      • Smith C.W.
      The alternative splicing program of differentiated smooth muscle cells involves concerted non-productive splicing of post-transcriptional regulators.
      ]
      Quaking (QKI)
      Porcine SMCsMYOCDAlternative splicingSMC QKI induces SMC differentiation to proliferative phenotype[
      • van der Veer E.P.
      • de Bruin R.G.
      • Kraaijeveld A.O.
      • de Vries M.R.
      • Bot I.
      • Pera T.
      • Segers F.M.
      • Trompet S.
      • van Gils J.M.
      • Roeten M.K.
      • Beckers C.M.
      • van Santbrink P.J.
      • Janssen A.
      • van Solingen C.
      • Swildens J.
      • de Boer H.C.
      • Peters E.A.
      • Bijkerk R.
      • Rousch M.
      • Doop M.
      • Kuiper J.
      • Schalij M.J.
      • van der Wal A.C.
      • Richard S.
      • van Berkel T.J.
      • Pickering J.G.
      • Hiemstra P.S.
      • Goumans M.J.
      • Rabelink T.J.
      • de Vries A.A.
      • Quax P.H.
      • Jukema J.W.
      • Biessen E.A.
      • van Zonneveld A.J.
      Quaking, an RNA-binding protein, is a critical regulator of vascular smooth muscle cell phenotype.
      ]
      Murine iPS-derived SMCsHDAC7Alternative splicingiPS QKI induces SMC differentiation to contractile phenotype[
      • Caines R.
      • Cochrane A.
      • Kelaini S.
      • Vila-Gonzalez M.
      • Yang C.
      • Eleftheriadou M.
      • Moez A.
      • Stitt A.W.
      • Zeng L.
      • Grieve D.J.
      • Margariti A.
      The RNA-binding protein QKI controls alternative splicing in vascular cells, producing an effective model for therapy.
      ]
      Murine ESC-derived VSMCsSMA, SM22, SM-MHC, MYOCD, SRF, MEF-2cReduces expressionQKI reduces VSMC transcriptional regulators during differentiation from stem cells[
      • Wu Y.
      • Li Z.
      • Yang M.
      • Dai B.
      • Hu F.
      • Yang F.
      • Zhu J.
      • Chen T.
      • Zhang L.
      MicroRNA-214 regulates smooth muscle cell differentiation from stem cells by targeting RNA-binding protein QKI.
      ]
      Serine/arginine-rich splicing factor 1 (SRSF1)
      Murine VSMC sΔ133p53Increases expressionSMC SRSF1 promotes neointima proliferation after wire-injured carotid artery[
      • Xie N.
      • Chen M.
      • Dai R.
      • Zhang Y.
      • Zhao H.
      • Song Z.
      • Zhang L.
      • Li Z.
      • Feng Y.
      • Gao H.
      • Wang L.
      • Zhang T.
      • Xiao R.P.
      • Wu J.
      • Cao C.M.
      SRSF1 promotes vascular smooth muscle cell proliferation through a Δ133p53/EGR1/KLF5 pathway.
      ]
      Human aortic SMCs
      Human aortic SMCsNUB1Increases stability and expressionSMC SRSF1 upregulates proliferation and migration of SMC[
      • Jiang W.
      • Zhao W.
      • Ye F.
      • Huang S.
      • Wu Y.
      • Chen H.
      • Zhou R.
      • Fu G.
      SNHG12 regulates biological behaviors of ox-LDL-induced HA-VSMCs through upregulation of SPRY2 and NUB1.
      ]
      Transformer-2 protein homolog beta (Tra2β)
      Rat aortic SMCsMYPTIAlternative splicingSMC Tra2β induces VSMC diversification between slow and fast smooth muscle phenotype[
      • Shukla S.
      • Fisher S.A.
      Tra2beta as a novel mediator of vascular smooth muscle diversification.
      ]
      Murine mesenteric artery SMCsMYPTIAlternative splicingSMC Tra2β reduces vasorelaxation[
      • Zheng X.
      • Reho J.J.
      • Wirth B.
      • Fisher S.A.
      TRA2β controls Mypt1 exon 24 splicing in the developmental maturation of mouse mesenteric artery smooth muscle.
      ]
      Rat VSMCsRA301/Tra2βOxidative stress induces Tra2β expressionSMC Tra2β induces cell stress and VSMC proliferation through ERK signaling pathway[
      • Tsukamoto Y.
      • Matsuo N.
      • Ozawa K.
      • Hori O.
      • Higashi T.
      • Nishizaki J.
      • Tohnai N.
      • Nagata I.
      • Kawano K.
      • Yutani C.
      • Hirota S.
      • Kitamura Y.
      • Stern D.M.
      • Ogawa S.
      Expression of a novel RNA-splicing factor, RA301/Tra2beta, in vascular lesions and its role in smooth muscle cell proliferation.
      ]
      VSMC, vascular smooth muscle cell; SMC, smooth muscle cell; iPS, induced pluripotent stem cell; ESC, embryonic stem cell; CCND1, Cylcin D1; PCNA, proliferating cell nuclear antigen; p27, Cyclin Dependent Kinase Inhibitor 1; Gata-6, GATA Binding Protein 6; SAT1, Spermidine/Spermine N1-Acetyltransferase 1; CDK2, Cyclin Dependent Kinase 2; sGCβ1, soluble Guanylate Cyclase beta 1; CRP, C-reactive protein; TNF-α, Tumor Necrosis Factor-alpha; TLR4, Toll Like Receptor 4; IQGAP1, IQ Motif Containing GTPase Activating Protein 1; Acta2, Actin Alpha 2, Smooth Muscle; SRF, Serum Response Factor; MEF2c, Myocyte Enhancer Factor 2C; Myocd, Myocardin; SMαA, smooth muscle alpha-actin; SM-MHC, Myosin Heavy Chain 11; Cbx3, Chromobox 3; Abi1, Abl Interactor 1; Dock7, Dedicator Of Cytokinesis 7; Atp2b4, ATPase Plasma Membrane Ca2+ Transporting 4; Dst, Dystonin; Pkm, Pyruvate Kinase M1/2; Actn1, Actinin Alpha 1; Tpm1, Tropomyosin 1; Itga7, Integrin Subunit Alpha 7; HDAC7, Histone Deacetylase 7; SM22, Transgelin; Δ133p53, p53 isoform; Nub1, Negative Regulator Of Ubiquitin Like Proteins 1; MYPTI, myosin phosphatase targeting subunit 1.
      In homeostatic conditions, HuR binds to the 3′ UTR of Regulator of G-protein signaling or soluble guanylate cyclase, increasing their stability and thus expression to regulate SMCs contraction and maintain blood pressure [
      • Martín-Garrido A.
      • González-Ramos M.
      • Griera M.
      • Guijarro B.
      • Cannata-Andia J.
      • Rodriguez-Puyol D.
      • Rodriguez-Puyol M.
      • Saura M.
      H2O2 regulation of vascular function through sGC mRNA stabilization by HuR.
      ,
      • Liu S.
      • Jiang X.
      • Lu H.
      • Xing M.
      • Qiao Y.
      • Zhang C.
      • Zhang W.
      HuR (human antigen R) regulates the contraction of vascular smooth muscle and maintains blood pressure.
      ]. HuR is also highly expressed in SMCs of neointimal lesions, where it stabilizes mRNAs encoding cell cycle proteins [
      • Pullmann Jr., R.
      • Juhaszova M.
      • López de Silanes I.
      • Kawai T.
      • Mazan-Mamczarz K.
      • Halushka M.K.
      • Gorospe M.
      Enhanced proliferation of cultured human vascular smooth muscle cells linked to increased function of RNA-binding protein HuR.
      ]. Indeed, upon PDGF stimulation of SMCs, an inducer of VSMC proliferation and migration, HuR translocates in the cytoplasm to bind to the 3’ UTR of its mRNA targets and therefore increasing expression levels of CDK2, CALM2, RPA2, SLC7A7, OSBLP2, PSMA6, and TAF9 causing a phenotypic switching of SMC into a proliferative phenotype [
      • Pullmann Jr., R.
      • Juhaszova M.
      • López de Silanes I.
      • Kawai T.
      • Mazan-Mamczarz K.
      • Halushka M.K.
      • Gorospe M.
      Enhanced proliferation of cultured human vascular smooth muscle cells linked to increased function of RNA-binding protein HuR.
      ]. Therefore, knockout of HuR enhanced VSMC contraction and reduced their proliferation (Fig. 2) [
      • Pullmann Jr., R.
      • Juhaszova M.
      • López de Silanes I.
      • Kawai T.
      • Mazan-Mamczarz K.
      • Halushka M.K.
      • Gorospe M.
      Enhanced proliferation of cultured human vascular smooth muscle cells linked to increased function of RNA-binding protein HuR.
      ,
      • Liu S.
      • Jiang X.
      • Lu H.
      • Xing M.
      • Qiao Y.
      • Zhang C.
      • Zhang W.
      HuR (human antigen R) regulates the contraction of vascular smooth muscle and maintains blood pressure.
      ].
      QKI expression levels also play a central part in SMC phenotype determination. QKI is poorly expressed in SMCs of healthy coronary arteries but is strongly induced in response to vascular injury, suggesting that the RNA-binding properties of QKI are repressed in contractile SMCs [
      • van der Veer E.P.
      • de Bruin R.G.
      • Kraaijeveld A.O.
      • de Vries M.R.
      • Bot I.
      • Pera T.
      • Segers F.M.
      • Trompet S.
      • van Gils J.M.
      • Roeten M.K.
      • Beckers C.M.
      • van Santbrink P.J.
      • Janssen A.
      • van Solingen C.
      • Swildens J.
      • de Boer H.C.
      • Peters E.A.
      • Bijkerk R.
      • Rousch M.
      • Doop M.
      • Kuiper J.
      • Schalij M.J.
      • van der Wal A.C.
      • Richard S.
      • van Berkel T.J.
      • Pickering J.G.
      • Hiemstra P.S.
      • Goumans M.J.
      • Rabelink T.J.
      • de Vries A.A.
      • Quax P.H.
      • Jukema J.W.
      • Biessen E.A.
      • van Zonneveld A.J.
      Quaking, an RNA-binding protein, is a critical regulator of vascular smooth muscle cell phenotype.
      ,
      • Caines R.
      • Cochrane A.
      • Kelaini S.
      • Vila-Gonzalez M.
      • Yang C.
      • Eleftheriadou M.
      • Moez A.
      • Stitt A.W.
      • Zeng L.
      • Grieve D.J.
      • Margariti A.
      The RNA-binding protein QKI controls alternative splicing in vascular cells, producing an effective model for therapy.
      ]. QKI is a critical post-transcriptional regulator of Myocardin (MYOCD), a transcriptional coactivator required for the proper expression of contraction-related genes such as SRF, SM22, Acta2, CALD1, Myh11 and CNN1 mediating the switch between contractile and non-contractile phenotypes [
      • van der Veer E.P.
      • de Bruin R.G.
      • Kraaijeveld A.O.
      • de Vries M.R.
      • Bot I.
      • Pera T.
      • Segers F.M.
      • Trompet S.
      • van Gils J.M.
      • Roeten M.K.
      • Beckers C.M.
      • van Santbrink P.J.
      • Janssen A.
      • van Solingen C.
      • Swildens J.
      • de Boer H.C.
      • Peters E.A.
      • Bijkerk R.
      • Rousch M.
      • Doop M.
      • Kuiper J.
      • Schalij M.J.
      • van der Wal A.C.
      • Richard S.
      • van Berkel T.J.
      • Pickering J.G.
      • Hiemstra P.S.
      • Goumans M.J.
      • Rabelink T.J.
      • de Vries A.A.
      • Quax P.H.
      • Jukema J.W.
      • Biessen E.A.
      • van Zonneveld A.J.
      Quaking, an RNA-binding protein, is a critical regulator of vascular smooth muscle cell phenotype.
      ,
      • Caines R.
      • Cochrane A.
      • Kelaini S.
      • Vila-Gonzalez M.
      • Yang C.
      • Eleftheriadou M.
      • Moez A.
      • Stitt A.W.
      • Zeng L.
      • Grieve D.J.
      • Margariti A.
      The RNA-binding protein QKI controls alternative splicing in vascular cells, producing an effective model for therapy.
      ]. Low expression of QKI favors the alternative splicing of the MYOCD pre-mRNA toward MYOCD_v3, a primary isoform expressed in contractile VSMCs, while QKI high expression led to the Myocd splice variant MYOCD_v1, an isoform enriched in proliferative VSMCs [
      • van der Veer E.P.
      • de Bruin R.G.
      • Kraaijeveld A.O.
      • de Vries M.R.
      • Bot I.
      • Pera T.
      • Segers F.M.
      • Trompet S.
      • van Gils J.M.
      • Roeten M.K.
      • Beckers C.M.
      • van Santbrink P.J.
      • Janssen A.
      • van Solingen C.
      • Swildens J.
      • de Boer H.C.
      • Peters E.A.
      • Bijkerk R.
      • Rousch M.
      • Doop M.
      • Kuiper J.
      • Schalij M.J.
      • van der Wal A.C.
      • Richard S.
      • van Berkel T.J.
      • Pickering J.G.
      • Hiemstra P.S.
      • Goumans M.J.
      • Rabelink T.J.
      • de Vries A.A.
      • Quax P.H.
      • Jukema J.W.
      • Biessen E.A.
      • van Zonneveld A.J.
      Quaking, an RNA-binding protein, is a critical regulator of vascular smooth muscle cell phenotype.
      ]. Furthermore, QKI-6 binds directly to intron 1 of HDAC7 after PDGF stimulation, to induce VSMC proliferation in conjunction with SRF and MYOCD (Fig. 3) [
      • Caines R.
      • Cochrane A.
      • Kelaini S.
      • Vila-Gonzalez M.
      • Yang C.
      • Eleftheriadou M.
      • Moez A.
      • Stitt A.W.
      • Zeng L.
      • Grieve D.J.
      • Margariti A.
      The RNA-binding protein QKI controls alternative splicing in vascular cells, producing an effective model for therapy.
      ].
      Several RBPs are known to maintain SMC contractile phenotype. For instance, transformer 2β (Tra2β) ensures the splicing of MYPT1, a gene involved in SMC differentiation from slow to fast contractile phenotype, allowing the vasorelaxation in blood vessels [
      • Shukla S.
      • Fisher S.A.
      Tra2beta as a novel mediator of vascular smooth muscle diversification.
      ,
      • Zheng X.
      • Reho J.J.
      • Wirth B.
      • Fisher S.A.
      TRA2β controls Mypt1 exon 24 splicing in the developmental maturation of mouse mesenteric artery smooth muscle.
      ]. Polypyrimidine Tract Binding protein 1 (PTBP1) mediates alternative splicing in SMCs, resulting in a contractile phenotype [
      • Llorian M.
      • Gooding C.
      • Bellora N.
      • Hallegger M.
      • Buckroyd A.
      • Wang X.
      • Rajgor D.
      • Kayikci M.
      • Feltham J.
      • Ule J.
      • Eyras E.
      • Smith C.W.
      The alternative splicing program of differentiated smooth muscle cells involves concerted non-productive splicing of post-transcriptional regulators.
      ]. DEAD-Box-Protein 5 (DDX-5) directly binds and maintains GATA-6 expression, a pivotal factor for maintaining SMCs contractile phenotype [
      • Fan Y.
      • Chen Y.
      • Zhang J.
      • Yang F.
      • Hu Y.
      • Zhang L.
      • Zeng C.
      • Xu Q.
      Protective role of RNA helicase DEAD-box protein 5 in smooth muscle cell proliferation and vascular remodeling.
      ].
      Conversely, some RBPs are actively involved in the alternative splicing events that shape the transcriptome of proliferative VSMCs. The splicing regulator Serine/arginine splicing factor 1 (SRSF1) is highly expressed in SMCs, and its expression is increased in a rat model of carotid artery injury [
      • Xie N.
      • Chen M.
      • Dai R.
      • Zhang Y.
      • Zhao H.
      • Song Z.
      • Zhang L.
      • Li Z.
      • Feng Y.
      • Gao H.
      • Wang L.
      • Zhang T.
      • Xiao R.P.
      • Wu J.
      • Cao C.M.
      SRSF1 promotes vascular smooth muscle cell proliferation through a Δ133p53/EGR1/KLF5 pathway.
      ]. SRSF1 induces alternative splicing of p53 to create Δ133p53, a transcript that activates Krüppel-like factor 5 (KLF5), facilitating the migration and proliferation of VSMCs, and thus the intimal thickening after vascular injury [
      • Xie N.
      • Chen M.
      • Dai R.
      • Zhang Y.
      • Zhao H.
      • Song Z.
      • Zhang L.
      • Li Z.
      • Feng Y.
      • Gao H.
      • Wang L.
      • Zhang T.
      • Xiao R.P.
      • Wu J.
      • Cao C.M.
      SRSF1 promotes vascular smooth muscle cell proliferation through a Δ133p53/EGR1/KLF5 pathway.
      ]. However, a recent report indicates that increased SRSF1 expression stabilizes the negative regulator of ubiquitin-like proteins 1 (NUB1) expression, a transcription factor known for its anti-proliferative effect in cancer, to reverse the SMC phenotype switch [
      • Jiang W.
      • Zhao W.
      • Ye F.
      • Huang S.
      • Wu Y.
      • Chen H.
      • Zhou R.
      • Fu G.
      SNHG12 regulates biological behaviors of ox-LDL-induced HA-VSMCs through upregulation of SPRY2 and NUB1.
      ,
      • Hosono T.
      • Tanaka T.
      • Tanji K.
      • Nakatani T.
      • Kamitani T.
      NUB1, an interferon-inducible protein, mediates anti-proliferative actions and apoptosis in renal cell carcinoma cells through cell-cycle regulation.
      ].
      With exposure to free cholesterol or oxidized LDL, SMCs switch to a macrophage-like phenotype, characterized by decreased expression of contractile genes and increase expression of macrophage markers (e.g. LGALS3 and CD68) embedding a newly acquired phagocytotic and efferocytotic function [
      • Bennett M.R.
      • Sinha S.
      • Owens G.K.
      Vascular smooth muscle cells in atherosclerosis.
      ]. The splicing RBP factor Muscle blind‐like splicing regulator 1 (MBNL1) is strongly reduced in the neointima of atherosclerotic arteries. Loss of MBNL1 results in alternative splicing of ABI1 mRNA and enhances the expression and function of KLF4 and contributes to a macrophage-like phenotype promoting oxidized phospholipid production [
      • Li Y.
      • Guo X.
      • Xue G.
      • Wang H.
      • Wang Y.
      • Wang W.
      • Yang S.
      • Ni Q.
      • Chen J.
      • Lv L.
      • Zhao Y.
      • Ye M.
      • Zhang L.
      RNA Splicing of the Abi1 Gene by MBNL1 contributes to macrophage-like phenotype modulation of vascular smooth muscle cell during atherogenesis.
      ].
      In late atherosclerosis, the formation of a necrotic core driven by deficient efferocytosis of SMC and macrophages critically contributes to plaque vulnerability. Autophagy, a major intracellular degradation system, plays a crucial role in this process and is tightly regulated by AMP-activated protein kinase (AMPK) [
      • He C.
      • Klionsky D.J.
      Regulation mechanisms and signaling pathways of autophagy.
      ]. HuR binds to and stabilizes the mRNAs of AMPKα1 and AMPKα2 [
      • Liu S.
      • Jiang X.
      • Cui X.
      • Wang J.
      • Liu S.
      • Li H.
      • Yang J.
      • Zhang C.
      • Zhang W.
      Smooth muscle-specific HuR knockout induces defective autophagy and atherosclerosis.
      ]. Crucially, the absence of HuR in a smooth muscle-specific HuR knockout mouse model of atherosclerosis led to defective autophagy, increased apoptosis and atherosclerotic plaque size [
      • Liu S.
      • Jiang X.
      • Cui X.
      • Wang J.
      • Liu S.
      • Li H.
      • Yang J.
      • Zhang C.
      • Zhang W.
      Smooth muscle-specific HuR knockout induces defective autophagy and atherosclerosis.
      ].

      6. RNA-binding proteins regulate immune cell function in atherosclerosis

      The atherosclerotic lesions are filled with monocytes, dendritic cells and T cells orchestrating the immune response [
      • Wolf D.
      • Ley K.
      Immunity and inflammation in atherosclerosis.
      ]. After the migration from the circulation into the intima of the vessel, monocytes are converted to macrophages. These cells will later transform into foam cells via the uptake of modified lipoproteins [
      • Wolf D.
      • Ley K.
      Immunity and inflammation in atherosclerosis.
      ]. QKI post-transcriptionally regulates monocyte to macrophage differentiation through regulating pre-mRNA splicing and transcript abundance in monocytes and macrophages [
      • de Bruin R.G.
      • Shiue L.
      • Prins J.
      • de Boer H.C.
      • Singh A.
      • Fagg W.S.
      • van Gils J.M.
      • Duijs J.M.
      • Katzman S.
      • Kraaijeveld A.O.
      • Böhringer S.
      • Leung W.Y.
      • Kielbasa S.M.
      • Donahue J.P.
      • van der Zande P.H.
      • Sijbom R.
      • van Alem C.M.
      • Bot I.
      • van Kooten C.
      • Jukema J.W.
      • Van Esch H.
      • Rabelink T.J.
      • Kazan H.
      • Biessen E.A.
      • Ares Jr., M.
      • van Zonneveld A.J.
      • van der Veer E.P.
      Quaking promotes monocyte differentiation into pro-atherogenic macrophages by controlling pre-mRNA splicing and gene expression.
      ]. The increased expression of QKI mRNAs in naive monocytes following recruitment to the lesion site could help to prime these cells and rapidly respond to the environmental pro-inflammatory triggers. Indeed, loss of QKI impaired monocyte adhesion, migration, and the capacity to adopt the macrophage phenotype (Fig. 3) [
      • de Bruin R.G.
      • Shiue L.
      • Prins J.
      • de Boer H.C.
      • Singh A.
      • Fagg W.S.
      • van Gils J.M.
      • Duijs J.M.
      • Katzman S.
      • Kraaijeveld A.O.
      • Böhringer S.
      • Leung W.Y.
      • Kielbasa S.M.
      • Donahue J.P.
      • van der Zande P.H.
      • Sijbom R.
      • van Alem C.M.
      • Bot I.
      • van Kooten C.
      • Jukema J.W.
      • Van Esch H.
      • Rabelink T.J.
      • Kazan H.
      • Biessen E.A.
      • Ares Jr., M.
      • van Zonneveld A.J.
      • van der Veer E.P.
      Quaking promotes monocyte differentiation into pro-atherogenic macrophages by controlling pre-mRNA splicing and gene expression.
      ]. Macrophages also expresses multiple metalloproteinases that degrade the extracellular matrix, weakening the plaque and making it prone to rupture. HuR absence in macrophages reduces Matrix metalloproteinase-9 (MMP-9) mRNA stabilization and protein production, suggesting that HuR promotes plaque instability [
      • Zhang J.
      • Modi Y.
      • Yarovinsky T.
      • Yu J.
      • Collinge M.
      • Kyriakides T.
      • Zhu Y.
      • Sessa W.C.
      • Pardi R.
      • Bender J.R.
      Macrophage β2 integrin-mediated, HuR-dependent stabilization of angiogenic factor-encoding mRNAs in inflammatory angiogenesis.
      ]. In human atherosclerotic plaques and circulating monocytes, TTP has been identified as one of the most highly expressed macrophage transcriptional regulators [
      • Patino W.D.
      • Kang J.G.
      • Matoba S.
      • Mian O.Y.
      • Gochuico B.R.
      • Hwang P.M.
      Atherosclerotic plaque macrophage transcriptional regulators are expressed in blood and modulated by tristetraprolin.
      ]. Therefore, global deletion of TTP results in a marked increase of aortic plaque in a mouse model of atherosclerosis by disrupting the recruitment of immune cells [
      • Kang J.G.
      • Amar M.J.
      • Remaley A.T.
      • Kwon J.
      • Blackshear P.J.
      • Wang P.Y.
      • Hwang P.M.
      Zinc finger protein tristetraprolin interacts with CCL3 mRNA and regulates tissue inflammation.
      ].
      Dendritic cells patrolling the arteries may absorb lipoprotein components for subsequent antigen presentation and produce chemokines and cytokines that might trigger further inflammation. Interestingly, PTBP1 deficiency in dendritic cells increases the frequency of activated CD4+ and CD8+T-cells suggesting a dysregulation in T Cell homeostasis [
      • Geng G.
      • Xu C.
      • Peng N.
      • Li Y.
      • Liu J.
      • Wu J.
      • Liang J.
      • Zhu Y.
      • Shi L.
      PTBP1 is necessary for dendritic cells to regulate T-cell homeostasis and antitumour immunity.
      ]. In parallel with monocytes, T cells are recruited to the vascular wall by mechanisms involving adhesion molecules and chemokines. Once activated, T cells contribute to lesion growth and plaque progression by secretion of proatherogenic mediators [
      • Wolf D.
      • Ley K.
      Immunity and inflammation in atherosclerosis.
      ]. For instance, HuR targets genes in multiple canonical pathways involved in T cell activation and differentiation. HuR mediates Th1, Th17 cell and CD4+ T cell plasticity by controlling transcripts of transcription factors and receptors (Fig. 2) [
      • Chen J.
      • Martindale J.L.
      • Abdelmohsen K.
      • Kumar G.
      • Fortina P.M.
      • Gorospe M.
      • Rostami A.
      • Yu S.
      RNA-binding protein HuR promotes Th17 cell differentiation and can Be targeted to reduce autoimmune neuroinflammation.
      ,
      • Techasintana P.
      • Davis J.W.
      • Gubin M.M.
      • Magee J.D.
      • Atasoy U.
      Transcriptomic-wide discovery of direct and indirect HuR RNA targets in activated CD4+ T cells.
      ]. However, whether these dendritic and T cell-mediated immune mechanisms in atherosclerosis are conserved remains to be demonstrated. Other RBPs are also known to regulate T-cell or B-cell homeostasis and deciphering their contribution to atherosclerosis will be the next challenge in resolving inflammation.

      7. RNA-binding proteins regulate inflammatory signaling

      Chemokines and cytokines are immunomodulatory molecules tightly balancing the equilibrium between physiology and pathophysiology. The infiltration of monocyte and neutrophil to vascular lesion sides is orchestrated by numerous chemokines and their counter partners' receptors [
      • Ramji D.P.
      • Davies T.S.
      Cytokines in atherosclerosis: key players in all stages of disease and promising therapeutic targets.
      ]. The regulation of their expression is tightly dependent on RNA binding proteins (Table 4). For instance, CCL2 and its receptor CCR2 regulate monocyte recruitment from the bone marrow to lesion side. Both CCL2 and CCR2 are targets of post-transcriptional RBP-mediated regulation. TTP binds to the ARE-rich 3′UTR of CCR2, by potentially promoting deadenylation, the poly(A) tail-shortening process, thereby reducing CCR2 expression [
      • Patial S.
      • Curtis 2nd, A.D.
      • Lai W.S.
      • Stumpo D.J.
      • Hill G.D.
      • Flake G.P.
      • Mannie M.D.
      • Blackshear P.J.
      Enhanced stability of tristetraprolin mRNA protects mice against immune-mediated inflammatory pathologies.
      ,
      • Saaoud F.
      • Wang J.
      • Iwanowycz S.
      • Wang Y.
      • Altomare D.
      • Shao Y.
      • Liu J.
      • Blackshear P.J.
      • Lessner S.M.
      • Murphy E.A.
      • Wang H.
      • Yang X.
      • Fan D.
      Bone marrow deficiency of mRNA decaying protein Tristetraprolin increases inflammation and mitochondrial ROS but reduces hepatic lipoprotein production in LDLR knockout mice.
      ]. Increased TTP also reduces CCL2 mRNA stability in an m6A-dependent manner resulting in transcript degradation, and protection against inflammation [
      • Xiao P.
      • Li M.
      • Zhou M.
      • Zhao X.
      • Wang C.
      • Qiu J.
      • Fang Q.
      • Jiang H.
      • Dong H.
      • Zhou R.
      TTP protects against acute liver failure by regulating CCL2 and CCL5 through m6A RNA methylation.
      ,
      • Zhang H.
      • Taylor W.R.
      • Joseph G.
      • Caracciolo V.
      • Gonzales D.M.
      • Sidell N.
      • Seli E.
      • Blackshear P.J.
      • Kallen C.B.
      mRNA-binding protein ZFP36 is expressed in atherosclerotic lesions and reduces inflammation in aortic endothelial cells.
      ]. In contrast, FXR1 in monocyte is required for upregulated CCL2 mRNA levels and to induce their migration and recruitment [
      • Le Tonqueze O.
      • Kollu S.
      • Lee S.
      • Al-Salah M.
      • Truesdell S.S.
      • Vasudevan S.
      Regulation of monocyte induced cell migration by the RNA binding protein, FXR1.
      ]. Similarly, endothelial HuR depletion drives CCL2 mRNA decreased expression (Fig. 2) [
      • Fu X.
      • Zhai S.
      • Yuan J.
      Endothelial HuR deletion reduces the expression of proatherogenic molecules and attenuates atherosclerosis.
      ]. CCL3 and CCL5 are other chemokines significantly increased in atherosclerotic lesions regulating further monocyte and neutrophil recruitment, accumulation, and therefore atherosclerosis development. In line with TTP anti-atherosclerotic role, CCL3, as well as other mediators triggering inflammation (e.g. TNF-α, CTSS), are negatively regulated by TTP in the mouse aorta [
      • Bollmann F.
      • Wu Z.
      • Oelze M.
      • Siuda D.
      • Xia N.
      • Henke J.
      • Daiber A.
      • Li H.
      • Stumpo D.J.
      • Blackshear P.J.
      • Kleinert H.
      • Pautz A.
      Endothelial dysfunction in tristetraprolin-deficient mice is not caused by enhanced tumor necrosis factor-α expression.
      ]. CCR1 (CCL3 receptor) and CCL5 are negatively regulated by TTP, partly by reduced m6A-mediated methylation [
      • Xiao P.
      • Li M.
      • Zhou M.
      • Zhao X.
      • Wang C.
      • Qiu J.
      • Fang Q.
      • Jiang H.
      • Dong H.
      • Zhou R.
      TTP protects against acute liver failure by regulating CCL2 and CCL5 through m6A RNA methylation.
      ,
      • Tiedje C.
      • Diaz-Muñoz M.D.
      • Trulley P.
      • Ahlfors H.
      • Laaß K.
      • Blackshear P.J.
      • Turner M.
      • Gaestel M.
      The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation.
      ]. CXCL1 and CXCL2 are chemokines involved in neutrophil-mediated inflammation and the development of plaque vulnerability [
      • Zernecke A.
      • Weber C.
      Chemokines in atherosclerosis: proceedings resumed.
      ]. In macrophages and myeloid cells, TTP negatively regulates CXCL1 and CXCL2 mRNA [
      • Ross E.A.
      • Smallie T.
      • Ding Q.
      • O'Neil J.D.
      • Cunliffe H.E.
      • Tang T.
      • Rosner D.R.
      • Klevernic I.
      • Morrice N.A.
      • Monaco C.
      • Cunningham A.F.
      • Buckley C.D.
      • Saklatvala J.
      • Dean J.L.
      • Clark A.R.
      Dominant suppression of inflammation via targeted mutation of the mRNA destabilizing protein tristetraprolin.
      ,
      • Brooks S.A.
      • Blackshear P.J.
      Tristetraprolin (TTP): interactions with mRNA and proteins, and current thoughts on mechanisms of action.
      ].
      Table 4Role of RNA-binding proteins in inflammation and oxidative stress.
      Tissue/Cells studiedTargetEffect on target expressionEffect of tissue-specific RBP in inflammation and oxidative stressRef.
      AU-rich element RNA-binding protein 1 (AUF1)
      Bovine aortic ECVCAM-1Increases stability and expressionEC AUF1 induces macrophage infiltration to the intima of atherosclerotic vessels[
      • Huang C.Y.
      • Shih C.M.
      • Tsao N.W.
      • Chen Y.H.
      • Li C.Y.
      • Chang Y.J.
      • Chang N.C.
      • Ou K.L.
      • Lin C.Y.
      • Lin Y.W.
      • Nien C.H.
      • Lin F.Y.
      GroEL1, from Chlamydia pneumoniae, induces vascular adhesion molecule 1 expression by p37(AUF1) in endothelial cells and hypercholesterolemic rabbit.
      ]
      Murine BMDMIL-10, IL-6, TNF-αDecreases stability and expressionMyeloid AUF1 subcellular localization-reduces LPS-induced inflammatory response[
      • Yu H.
      • Sun Y.
      • Haycraft C.
      • Palanisamy V.
      • Kirkwood K.L.
      MKP-1 regulates cytokine mRNA stability through selectively modulation subcellular translocation of AUF1.
      ]
      HUVECsNeat1Increased stability and expressionEC AUF1 positively regulates inflammation-activated endothelium in atherosclerotic vascular disease[
      • Vlachogiannis N.I.
      • Sachse M.
      • Georgiopoulos G.
      • Zormpas E.
      • Bampatsias D.
      • Delialis D.
      • Bonini F.
      • Galyfos G.
      • Sigala F.
      • Stamatelopoulos K.
      • Gatsiou A.
      • Stellos K.
      Adenosine-to-inosine Alu RNA editing controls the stability of the pro-inflammatory long noncoding RNA NEAT1 in atherosclerotic cardiovascular disease.
      ]
      Human monocytesIL-10, TAK1Increases expression by activating IkappaB kinase complex and induces TAK1 mRNA translationMyeloid AUF1 contributes to anti-inflammatory, LPS-induced IL-10 production and TAK1-mediated NFκB signaling[
      • Sarkar S.
      • Han J.
      • Sinsimer K.S.
      • Liao B.
      • Foster R.L.
      • Brewer G.
      • Pestka S.
      RNA-binding protein AUF1 regulates lipopolysaccharide-induced IL10 expression by activating IkappaB kinase complex in monocytes.
      ]
      Cell Cycle Associated Protein 1 (CAPRIN1)
      Murine monocytes,STAT1Increases stability and expressionMyeloid CAPRIN1 promotes IFN-γ innate immune responses in macrophages from mice infected with Listeria monocytogenes[
      • Xu H.
      • Jiang Y.
      • Xu X.
      • Su X.
      • Liu Y.
      • Ma Y.
      • Zhao Y.
      • Shen Z.
      • Huang B.
      • Cao X.
      Inducible degradation of lncRNA Sros1 promotes IFN-γ-mediated activation of innate immune responses by stabilizing Stat1 mRNA.
      ]
      Human kidney cells
      Cold-inducible RNA-binding protein (CIRP)
      Murine lung tissueBiP, pIRE1α, sXBP1, CHOP, c-Casp-12, IL-6, IL-1β, MIP2, KC, MPOIncreases expressionLung CIRBP1 increases ER stress-mediated apoptosis and inflammation in acute lung injury in a murine sepsis model[
      • Khan M.M.
      • Yang W.L.
      • Brenner M.
      • Bolognese A.C.
      • Wang P.
      Cold-inducible RNA-binding protein (CIRP) causes sepsis-associated acute lung injury via induction of endoplasmic reticulum stress.
      ]
      Human liver cellsTLR4, gp91, p47, Fis-1Increases expressionHepatic CIRBP1 induces oxidative stress and mitochondrial dysfunction in liver ischemia‐reperfusion injury[
      • Liu W.
      • Fan Y.
      • Ding H.
      • Han D.
      • Yan Y.
      • Wu R.
      • Lv Y.
      • Zheng X.
      Normothermic machine perfusion attenuates hepatic ischaemia-reperfusion injury by inhibiting CIRP-mediated oxidative stress and mitochondrial fission.
      ]
      UCP2, TFAMDecreases expression
      Murine liver tissueIL-6, TNF-αIncreases expression.Hepatic CIRBP1 and released CIRP from macrophages induces cytokine production attenuating organ damage in hemorrhage and sepsis[
      • Qiang X.
      • Yang W.L.
      • Wu R.
      • Zhou M.
      • Jacob A.
      • Dong W.
      • Kuncewitch M.
      • Ji Y.
      • Yang H.
      • Wang H.
      • Fujita J.
      • Nicastro J.
      • Coppa G.F.
      • Tracey K.J.
      • Wang P.
      Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis.
      ]
      Murine macrophagesIL-6RSecreted CRP1 binds to IL-6R initiating downstream signalingMyeloid CIRBP1 promotes macrophage endotoxin tolerance and M2 polarization in LPS-induced sepsis[
      • Zhou M.
      • Aziz M.
      • Denning N.L.
      • Yen H.T.
      • Ma G.
      • Wang P.
      Extracellular CIRP induces macrophage endotoxin tolerance through IL-6R-mediated STAT3 activation.
      ]
      Human antigen R (HuR)
      HUVECsVCAM1, ICAM1Increases expressionShear stress-induced EC HuR. HuR increases adhesion molecule expression and monocyte binding to LPS-response[
      • Rhee W.J.
      • Ni C.W.
      • Zheng Z.
      • Chang K.
      • Jo H.
      • Bao G.
      HuR regulates the expression of stress-sensitive genes and mediates inflammatory response in human umbilical vein endothelial cells.
      ]
      Murine and human ECCD62E, CTSSIncreases stability and expressionEC HuR increases EC activation and monocyte recruitment[
      • Bibli S.I.
      • Hu J.
      • Sigala F.
      • Wittig I.
      • Heidler J.
      • Zukunft S.
      • Tsilimigras D.I.
      • Randriamboavonjy V.
      • Wittig J.
      • Kojonazarov B.
      • Schürmann C.
      • Siragusa M.
      • Siuda D.
      • Luck B.
      • Abdel Malik R.
      • Filis K.A.
      • Zografos G.
      • Chen C.
      • Wang D.W.
      • Pfeilschifter J.
      • Brandes R.P.
      • Szabo C.
      • Papapetropoulos A.
      • Fleming I.
      Cystathionine γ lyase sulfhydrates the RNA binding protein human antigen R to preserve endothelial cell function and delay atherogenesis.
      ]
      Murine spleen, aorta, BMDM and VSMCsHuRIL-19 decreases HuR stability and expressionIL-19 reduces atherosclerotic plaque area by reducing HuR and inflammatory gene expression[
      • Ray M.
      • Gabunia K.
      • Vrakas C.N.
      • Herman A.B.
      • Kako F.
      • Kelemen S.E.
      • Grisanti L.A.
      • Autieri M.V.
      Genetic deletion of IL-19 (Interleukin-19) exacerbates atherogenesis in Il19-/-×Ldlr-/- double knockout mice by dysregulation of mRNA stability protein HuR (human antigen R).
      ]
      Murine embryonic fibroblastIL-β, TNF-α, TGF-β, MMP9, COL1A1, COL1A2, COL3A1, αSMAIncreases expressionFibroblast HuR induces inflammation and fibrogenesis[
      • Govindappa P.K.
      • Patil M.
      • Garikipati V.N.S.
      • Verma S.K.
      • Saheera S.
      • Narasimhan G.
      • Zhu W.
      • Kishore R.
      • Zhang J.
      • Krishnamurthy P.
      Targeting exosome-associated human antigen R attenuates fibrosis and inflammation in diabetic heart.
      ]
      Murine BMDM and aortaHuRlncRNA MAARS retains HuR in the nucleusMyeloid HuR induces efferocytosis[
      • Simion V.
      • Zhou H.
      • Haemmig S.
      • Pierce J.B.
      • Mendes S.
      • Tesmenitsky Y.
      • Pérez-Cremades D.
      • Lee J.F.
      • Chen A.F.
      • Ronda N.
      • Papotti B.
      • Marto J.A.
      • Feinberg M.W.
      A macrophage-specific lncRNA regulates apoptosis and atherosclerosis by tethering HuR in the nucleus.
      ]
      Human gingival ECIL-6Increases stability and expressionEC HuR increases inflammatory responses in periodontitis[
      • Ouhara K.
      • Munenaga S.
      • Kajiya M.
      • Takeda K.
      • Matsuda S.
      • Sato Y.
      • Hamamoto Y.
      • Iwata T.
      • Yamasaki S.
      • Akutagawa K.
      • Mizuno N.
      • Fujita T.
      • Sugiyama E.
      • Kurihara H.
      The induced RNA-binding protein, HuR, targets 3′-UTR region of IL-6 mRNA and enhances its stabilization in periodontitis.
      ]
      Murine BMDMMcf2Increases expressionMyeloid HuR increases Dab1-mediated Rac1 activation and efferocytosis[
      • Crown S.B.
      • Ilkayeva O.R.
      • Darville L.
      • Kolluru G.K.
      • Rymond C.C.
      • Gerlach B.D.
      • Zheng Z.
      • Kuriakose G.
      • Kevil C.G.
      • Koomen J.M.
      • Cleveland J.L.
      • Muoio D.M.
      • Tabas I.
      Macrophage metabolism of apoptotic cell-derived arginine promotes continual efferocytosis and resolution of injury.
      ]
      Murine BMDMTNF-αReduces stability of mRNA by recruiting destabilizing RBPMyeloid HuR reduces inflammation and hepatic cell damage[
      • Katsanou V.
      • Papadaki O.
      • Milatos S.
      • Blackshear P.J.
      • Anderson P.
      • Kollias G.
      • Kontoyiannis D.L.
      HuR as a negative posttranscriptional modulator in inflammation.
      ]
      Murine naïve CD4+ T cellsIL-6Rα, cMafIncreases stability and expressionMyeloid HuR induces Th17 differentiation and IL-22 production[
      • Yu S.
      • Tripod M.
      • Atasoy U.
      • Chen J.
      HuR plays a positive role to strengthen the signaling pathways of CD4+ T cell activation and Th17 cell differentiation.
      ]
      Murine ECs14-3-3ζIncreases translation and expressionEC HuR induces intestine wound healing and cell migration[
      • Hansraj N.Z.
      • Xiao L.
      • Wu J.
      • Chen G.
      • Turner D.J.
      • Wang J.Y.
      • Rao J.N.
      Posttranscriptional regulation of 14-3-3ζ by RNA-binding protein HuR modulating intestinal epithelial restitution after wounding.
      ]
      Fragile-X mental retardation autosomal 1 (FXR1)
      Human VSMCICAM-1, IL-1β, MCP-1, TNF-α, HuRDecreases stability and expressionSMC FXR1 reduces inflammation and VSMC proliferation in vascular atherosclerotic disease[
      • Herman A.B.
      • Vrakas C.N.
      • Ray M.
      • Kelemen S.E.
      • Sweredoski M.J.
      • Moradian A.
      • Haines D.S.
      • Autieri M.V.
      FXR1 is an IL-19-responsive RNA-binding protein that destabilizes pro-inflammatory transcripts in vascular smooth muscle cells.
      ]
      Human MonocytesIL-1β, CCL2Increases expressionMyeloid FXR1 induces monocyte cell migration.[
      • Le Tonqueze O.
      • Kollu S.
      • Lee S.
      • Al-Salah M.
      • Truesdell S.S.
      • Vasudevan S.
      Regulation of monocyte induced cell migration by the RNA binding protein, FXR1.
      ]
      Heterogeneous nuclear ribonucleoprotein K (hnRNPK1)
      Human MonocytesIP-10Increases stability and expressionMyeloid hnRNPK1 increases monocyte activation[
      • Natarajan K.
      • Sundaramoorthy A.
      • Shanmugam N.
      HnRNPK and lysine specific histone demethylase-1 regulates IP-10 mRNA stability in monocytes.
      ]
      Human ECUCP2Suppresses translationEC hnRNPK1 reduces ROS production[
      • Tahir T.A.
      • Singh H.
      • Brindle N.P.
      The RNA binding protein hnRNP-K mediates post-transcriptional regulation of uncoupling protein-2 by angiopoietin-1.
      ]
      Quaking (QKI)
      Murine monocytes/macrophageNRF2, HMOX1, NQO1, GCLCIncreases expressionMyeloid QKI reduces ROS production in macrophages in chronic inflammatory disease[
      • Wang W.
      • Zhai D.
      • Bai Y.
      • Xue K.
      • Deng L.
      • Ma L.
      • Du T.
      • Ye Z.
      • Qu D.
      • Xiang A.
      • Chen G.
      • Zhao Y.
      • Wang L.
      • Lu Z.
      Loss of QKI in macrophage aggravates inflammatory bowel disease through amplified ROS signaling and microbiota disproportion.
      ]
      NOX2, p22, Keap1Reduces expression
      SUB1 homolog (SUB1)
      Murine macrophagesTNF-α, IL-β, CCL2, NOS2Increases expressionMyeloid Sub1 induces macrophage infiltration and enhances M1 macrophage phenotype in murine atherosclerosis models[
      • Liu Liang
      The anti-inflammatory effect of miR-16 through targeting C- reactive protein is regulated by HuR in vascular smooth muscle cells.
      ]
      Cytotoxic granule-associated RNA-binding protein (TIA1)
      Murine peritoneal macrophagesTNF-αReduces translation and expressionMyeloid TIA1 attenuates LPS-induced endotoxin shock[
      • Piecyk M.
      • Wax S.
      • Beck A.R.
      • Kedersha N.
      • Gupta M.
      • Maritim B.
      • Chen S.
      • Gueydan C.
      • Kruys V.
      • Streuli M.
      • Anderson P.
      TIA-1 is a translational silencer that selectively regulates the expression of TNF-alpha.
      ]
      Murine embryonic fibroblasts and colorectal cellsCox-2Reduces translation and expressionMyeloid TIA1 reduces prostaglandin expression[
      • Dixon D.A.
      • Balch G.C.
      • Kedersha N.
      • Anderson P.
      • Zimmerman G.A.
      • Beauchamp R.D.
      • Prescott S.M.
      Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1.
      ]
      Y-box protein 1 (YB-1)
      Human macrophagesCD36Promotes decay and reduces expression independent of transcriptionMyeloid YB-1 reduces lipid deposition in LDL-stimulated macrophages[
      • Cao X.
      • Zhu N.
      • Li L.
      • Zhang Y.
      • Chen Y.
      • Zhang J.
      • Li J.
      • Gao C.
      Y-box binding protein 1 regulates ox-LDL mediated inflammatory responses and lipid uptake in macrophages.
      ]
      Human T lymphocytes, rat mesangial cellsIL-10Increases expressionRenal YB1 reduces renal damage and monocyte infiltration after ischemia-reperfusion injury[
      • Wang J.
      • Djudjaj S.
      • Gibbert L.
      • Lennartz V.
      • Breitkopf D.M.
      • Rauen T.
      • Hermert D.
      • Martin I.V.
      • Boor P.
      • Braun G.S.
      • Floege J.
      • Ostendorf T.
      • Raffetseder U.
      YB-1 orchestrates onset and resolution of renal inflammation via IL10 gene regulation.
      ]
      Tristetraprolin (TTP)
      Human monocytesTNF-α, p21, EGR1, FOSIncreases binding and reduces expressionMyeloid TTP reduces macrophage transcriptional regulators in atherosclerosis[
      • Patino W.D.
      • Kang J.G.
      • Matoba S.
      • Mian O.Y.
      • Gochuico B.R.
      • Hwang P.M.
      Atherosclerotic plaque macrophage transcriptional regulators are expressed in blood and modulated by tristetraprolin.
      ]
      Murine BMDMIL-1β, CXCL2Reduces expressionMyeloid TTP reduces immune cell infiltration in murine models of chronic inflammatory disease[
      • Patial S.
      • Curtis 2nd, A.D.
      • Lai W.S.
      • Stumpo D.J.
      • Hill G.D.
      • Flake G.P.
      • Mannie M.D.
      • Blackshear P.J.
      Enhanced stability of tristetraprolin mRNA protects mice against immune-mediated inflammatory pathologies.
      ]
      Murine peritoneal macrophages and liver tissueTNF-α, SAA1, CCR2Reduces expressionMyeloid and hepatic TTP reduces inflammation in LPS-stimulates macrophages and mitochondrial reactive oxygen species production[
      • Saaoud F.
      • Wang J.
      • Iwanowycz S.
      • Wang Y.
      • Altomare D.
      • Shao Y.
      • Liu J.
      • Blackshear P.J.
      • Lessner S.M.
      • Murphy E.A.
      • Wang H.
      • Yang X.
      • Fan D.
      Bone marrow deficiency of mRNA decaying protein Tristetraprolin increases inflammation and mitochondrial ROS but reduces hepatic lipoprotein production in LDLR knockout mice.
      ]
      SREBF1Increases expression
      Human hepatic cellsCCL2, CCL5Reduces stability through m6A-mediated methylationHepatic TTP reduces macrophage infiltration in murine acute liver failure model[
      • Xiao P.
      • Li M.
      • Zhou M.
      • Zhao X.
      • Wang C.
      • Qiu J.
      • Fang Q.
      • Jiang H.
      • Dong H.
      • Zhou R.
      TTP protects against acute liver failure by regulating CCL2 and CCL5 through m6A RNA methylation.
      ]
      Human arterial EC and monocytesMCP-1, IL-6, NF-κBIncreases binding and reduces expressionEC and myeloid TTP reduces EC inflammation and atherosclerotic lesions[
      • Zhang H.
      • Taylor W.R.
      • Joseph G.
      • Caracciolo V.
      • Gonzales D.M.
      • Sidell N.
      • Seli E.
      • Blackshear P.J.
      • Kallen C.B.
      mRNA-binding protein ZFP36 is expressed in atherosclerotic lesions and reduces inflammation in aortic endothelial cells.
      ]
      Murine BMDMTNF-α, CXCL10, GDF15, Dusp1, Ier3, Tnfaip3Reduces stability, translation, and expressionMyeloid TTP reduces inflammatory gene expression and modulates apoptosis in LPS-stimulated macrophages[
      • Tiedje C.
      • Diaz-Muñoz M.D.
      • Trulley P.
      • Ahlfors H.
      • Laaß K.
      • Blackshear P.J.
      • Turner M.
      • Gaestel M.
      The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation.
      ]
      Murine BMDMCXCL1, IL-10, TNF-αReduces expression by degradationMyeloid TTP reduces inflammation in LPS-stimulated macrophages[
      • Ross E.A.
      • Smallie T.
      • Ding Q.
      • O'Neil J.D.
      • Cunliffe H.E.
      • Tang T.
      • Rosner D.R.
      • Klevernic I.
      • Morrice N.A.
      • Monaco C.
      • Cunningham A.F.
      • Buckley C.D.
      • Saklatvala J.
      • Dean J.L.
      • Clark A.R.
      Dominant suppression of inflammation via targeted mutation of the mRNA destabilizing protein tristetraprolin.
      ]
      Murine BMDMIL-1α, TNF-αReduces stability and expressionIL-10-mediated myeloid TTP expression reduces inflammation in LPS-stimulated macrophages[
      • Schaljo B.
      • Kratochvill F.
      • Gratz N.
      • Sadzak I.
      • Sauer I.
      • Hammer M.
      • Vogl C.
      • Strobl B.
      • Müller M.
      • Blackshear P.J.
      • Poli V.
      • Lang R.
      • Murray P.J.
      • Kovarik P.
      Tristetraprolin is required for full anti-inflammatory response of murine macrophages to IL-10.
      ]
      Murine peritoneal and blood macrophagesCD36Increases CD36 mRNA decay by binding to the 3′UTRMyeloid TTP reduces oxLDL uptake, intracellular cholesterol content and foam-cell formation[
      • Dai X.Y.
      • Cai Y.
      • Sun W.
      • Ding Y.
      • Wang W.
      • Kong W.
      • Tang C.
      • Zhu Y.
      • Xu M.J.
      • Wang X.
      Intermedin inhibits macrophage foam-cell formation via tristetraprolin-mediated decay of CD36 mRNA.
      ]
      HUVEC and human macrophagesGILZReduces expressionEC and myeloid TTP reduces inflammatory cell activation in vascular disease[
      • Hahn R.T.
      • Hoppstädter J.
      • Hirschfelder K.
      • Hachenthal N.
      • Diesel B.
      • Kessler S.M.
      • Huwer H.
      • Kiemer A.K.
      Downregulation of the glucocorticoid-induced leucine zipper (GILZ) promotes vascular inflammation.
      ]
      Human kidney cells and monocytesNLRP3Reduces expression by binding to the 3′UTR of NLRP3 mRNARenal and myeloid TTP reduces IL-1β production by regulating NLRP3 inflammasome[
      • Haneklaus M.
      • Neil J.D.
      • Clark A.R.
      • Masters S.L.
      • Neill L.A.J.
      The RNA-binding protein Tristetraprolin (TTP) is a critical negative regulator of the NLRP3 inflammasome.
      ]
      Murine BMDMTNF-αReduces stability and expressionMyeloid TTP reduces cytokine production and LPS-induced organ damage in mice.[
      • Qiu L.Q.
      • Stumpo D.J.
      • Blackshear P.J.
      Myeloid-specific tristetraprolin deficiency in mice results in extreme lipopolysaccharide sensitivity in an otherwise minimal phenotype.
      ]
      Murine BMDMTNF-α, IL-10Reduces stability and expressionMyeloid TTP reduces inflammation in LPS-stimulated macrophages[
      • Stoecklin G.
      • Tenenbaum S.A.
      • Mayo T.
      • Chittur S.V.
      • George A.D.
      • Baroni T.E.
      • Blackshear P.J.
      • Anderson P.
      Genome-wide analysis identifies interleukin-10 mRNA as target of tristetraprolin.
      ]
      Murine adipocytesIL-6, MCP-1, IL-1βReduces expressionAdipose TTP reduces LPS-stimulated inflammation in obesity[
      • Brahma P.K.
      • Zhang H.
      • Murray B.S.
      • Shu F.J.
      • Sidell N.
      • Seli E.
      • Kallen C.B.
      The mRNA binding protein Zfp36 is upregulated by β-adrenergic stimulation and represses IL-6 production in 3T3-L1 adipocytes.