RNA-binding proteins in vascular inflammation and atherosclerosis

Marco Sachse; Simon Tual-Chalot; Giorgia Ciliberti; Michael Amponsah-Offeh; Kimon Stamatelopoulos; Aikaterini Gatsiou; Konstantinos Stellos

doi:10.1016/j.atherosclerosis.2023.01.008

RNA-binding proteins in vascular inflammation and atherosclerosis

Marco Sachse ¹
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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Simon Tual-Chalot ¹
Author Footnotes
1 These authors contributed equally as first-authors.
Simon Tual-Chalot
Correspondence
Corresponding author.
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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
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
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
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
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
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.
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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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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 [

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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) [

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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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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 [

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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 [

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Fig. 1Schematic drawing of RNA-binding proteins regulating RNA fate.
Show full caption
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).
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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 [

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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 [

[8]

Treiber T.
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[24]

Ding Y.
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Zhang S.
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Pan X.
Zhu X.

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,

[28]

Gerstberger S.
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,

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,

[32]

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 [

[24]

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.

,

[28]

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-genicity	Model	Targets/Genes regulated	Effect on target/gene expression	Effect of tissue-specific RBP in atherosclerotic disease	Ref.
Human antigen R (HuR)
Pro	EC-specific HuR knockout in ApoE^−/− mouse	IL-6, IL-8, IL-1β, CCL2, CXCL1, CXCL12, VCAM, ICAM, SELE, CXCR2, SELP, CCR1, IL-6R	Increases expression.	EC HuR increases atherosclerotic surface area and monocyte recruitment onto vascular wall.	[ [42] Fu X. Zhai S. Yuan J. Endothelial HuR deletion reduces the expression of proatherogenic molecules and attenuates atherosclerosis. Int. Immunopharm. 2018 Dec; 65 (Epub 2018 Oct 17. PMID: 30340104): 248-255https://doi.org/10.1016/j.intimp.2018.09.023 Crossref PubMed Scopus (6) Google Scholar ]
Anti	SMC-specific HuR knockout mouse	RGS2, RGS4, RGS5	Increases stability.	VSMC HuR reduces systolic blood pressure and contractility of VSMC	[ [80] 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. Arterioscler. Thromb. Vasc. Biol. 2020 Apr; 40 (Epub 2020 Feb 20. PMID: 32075416): 943-957https://doi.org/10.1161/ATVBAHA.119.313897 Crossref PubMed Scopus (12) Google Scholar ]
Anti	SMC-specific HuR knockout mouse	AMPKα1, AMPKα2	Increases stability and translation.	VSMC HuR reduces plaque area, macrophage content and plaque vulnerability.	[ [93] 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. Cell Death Dis. 2021 Apr 9; 12 (PMID: 33837179; PMCID: PMC8035143): 385https://doi.org/10.1038/s41419-021-03671-2 Crossref PubMed Scopus (6) Google Scholar ]
Quaking (QKI)
Pro	Transplanted bone marrow from mice with reduced levels of QKI into LDLR^−/− mouse	Splicing: 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.	[ [57] 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. Nat. Commun. 2016 Mar 31; 7 (PMID: 27029405; PMCID: PMC4821877)10846https://doi.org/10.1038/ncomms10846 Crossref PubMed Scopus (70) Google Scholar ]
SUB1 homolog (SUB1)
Pro	Myeloid‐specific SUB1 knockout in ApoE^−/− mouse	Irf1	Increases expression.	Myeloid SUB1 increases atherosclerotic lesion area, reduced collagen and decrease anti-inflammatory M2 polarized macrophage content.	[ [142] 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. Adv. Sci. 2021 Oct; 8 (Epub 2021 Aug 10. PMID: 34378353; PMCID: PMC8498911)e2004162https://doi.org/10.1002/advs.202004162 Crossref Scopus (4) Google Scholar ]
Tristetraprolin (TTP)
Anti	TTP knockout mouse	S1008A, CTSS, VCAM-1, ICAM-1, SPP1, MIP-1α, TNF-α, CD68, NOX2	Decreases stability (NOX2) and expression	TTP reduces endothelial dysfunction and macrophage infiltration into the intima.	[ [46] 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. J. Biol. Chem. 2014 May 30; 289 (Epub 2014 Apr 11. PMID: 24727475; PMCID: PMC4140920): 15653-15665https://doi.org/10.1074/jbc.M114.566984 Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar ]
Anti	TTP knockout mouse in ApoE^−/− mouse	CCL3	Reduces mRNA stability and expression.	TTP reduces atherosclerotic plaque area.	[ [96] 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. J. Immunol. 2011 Sep 1; 187 (Epub 2011 Jul 22. PMID: 21784977; PMCID: PMC3159726): 2696-2701https://doi.org/10.4049/jimmunol.1101149 Crossref PubMed Scopus (40) Google Scholar ]

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.

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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 [

[33]

Zhang X.
Sessa W.C.
Fernández-Hernando C.

Endothelial transcytosis of lipoproteins in atherosclerosis.

,

[34]

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 [

[35]

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.

,

[36]

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) [

[37]

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.

,

[38]

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 [

[39]

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.

,

[40]

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 [

[35]

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.

,

[41]

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 [

[35]

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.

,

[41]

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 [

[36]

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) [

[42]

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 [

[43]

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.

,

[44]

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 [

[45]

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 [

[46]

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.

,

[47]

Blackshear P.J.

Tristetraprolin and other CCCH tandem zinc-finger proteins in the regulation of mRNA turnover.

].

Fig. 2RNA-binding protein HuR contribution to atherosclerosis.
Show full caption
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.
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Loss of vascular integrity is another hallmark of endothelial activation occurring in atherosclerosis [

[3]

Libby P.
Buring J.E.
Badimon L.
Hansson G.K.
Deanfield J.
Bittencourt M.S.
Tokgözoğlu L.
Lewis E.F.

Atherosclerosis.

,

[6]

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 [

[48]

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 [

[49]

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 [

[50]

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 [

[50]

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) [

[50]

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. 3RNA-binding protein QKI contribution to atherosclerosis.
Show full caption
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.
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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 [

[3]

Libby P.
Buring J.E.
Badimon L.
Hansson G.K.
Deanfield J.
Bittencourt M.S.
Tokgözoğlu L.
Lewis E.F.

Atherosclerosis.

,

[51]

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 [

[2]

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 [

[52]

Tall A.R.
Yvan-Charvet L.
Terasaka N.
Pagler T.
Wang N.

HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis.

,

[53]

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 [

[54]

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.

,

[55]

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 [

[56]

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) [

[56]

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 [

[57]

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) [

[57]

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 specificity	Target	Effect on target expression	Effect of tissue-specific RBP in metabolism and atherosclerosis	Ref.
Cold-inducible RNA-binding protein (CIRP)
Murine lung tissue	iNOS, 4-HNE	Increases expression	CIRP increases lipid peroxidation and oxidative stress in acute lung injury in a murine sepsis model	[ [143] 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. Sci. Rep. 2017 Jan 27; 7 (PMID: 28128330; PMCID: PMC5269663)41363https://doi.org/10.1038/srep41363 Crossref Scopus (51) Google Scholar ]
Human antigen R (HuR)
Human hepatic cells and monocytes	ABCA1	Increases expression independent of stability	Myeloid HuR increases cholesterol efflux to ApoAI	[ [56] 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. J. Lipid Res. 2014 Jun; 55 (Epub 2014 Apr 11. PMID: 24729624; PMCID: PMC4031938): 1066-1076https://doi.org/10.1194/jlr.M044925 Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar ]
Murine liver tissue, murine hepatoma cell	ApoB	Alternative splicing	Hepatic HuR increases ATP synthesis and lipid transport	[ [59] 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. Nat. Commun. 2020 Jun 16; 11 (PMID: 32546794; PMCID: PMC7298042): 3067https://doi.org/10.1038/s41467-020-16918-x Crossref PubMed Scopus (26) Google Scholar ]
Murine liver tissue, murine hepatoma cell	Cycs, Ndufb6, UqcrbB	Increases expression	Hepatic HuR increases ATP synthesis and lipid transport
Murine liver tissue, Human hepatoma cells	LDLR	Increases stability and expression	Hepatic HuR reduces triglyceride content in serum and liver	[ [67] 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. Arterioscler. Thromb. Vasc. Biol. 2018 Oct; 38 (PMID: 30354208; PMCID: PMC6206879): 2448-2459https://doi.org/10.1161/ATVBAHA.118.311122 Crossref PubMed Scopus (18) Google Scholar ]
Murine adipocytes and adipose tissue	ATGL	Increases stability, expression and translation	Adipose HuR reduces obesity through regulation of lipolysis and insulin resistance	[ [76] 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. Nat. Commun. 2019 May 30; 10 (PMID: 31147543; PMCID: PMC6542850): 2375https://doi.org/10.1038/s41467-019-10348-0 Crossref PubMed Scopus (35) Google Scholar ]
Human and mouse preadipocyte	Insig1	Increases stability and expression	Adipose HuR reduces adipogenesis through regulation of glucose intolerance and insulin resistance	[ [77] 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. Nat. Commun. 2020 Jan 10; 11 (PMID: 31924774; PMCID: PMC6954112): 213https://doi.org/10.1038/s41467-019-14001-8 Crossref PubMed Scopus (44) Google Scholar ]
Fragile-X mental retardation autosomal 1 (FXR1)
Murine liver cells	ApoM	Reduces expression	Hepatic FXR1 promotes atherogenesis	[ [65] Yang L. Li T. LncRNA TUG1 regulates ApoM to promote atherosclerosis progression through miR-92a/FXR1 axis. J. Cell Mol. Med. 2020 Aug; 24 (Epub 2020 Jun 28. PMID: 32597038; PMCID: PMC7412710): 8836-8848https://doi.org/10.1111/jcmm.15521 Crossref PubMed Scopus (14) Google Scholar ]
Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1)
Human hepatic cells	HMGCR	Alternative splicing	Hepatic HNRNPA1 increases LDL-uptake and cellular ApoB expression	[ [69] 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. Hum. Mol. Genet. 2014 Jan 15; 23 (Epub 2013 Sep 2. PMID: 24001602; PMCID: PMC3869353): 319-332https://doi.org/10.1093/hmg/ddt422 Crossref PubMed Scopus (45) Google Scholar ]
Murine satellite cells	PGC1a, CD36, CPT1b	Increases translation and expression	Satellite cell HNRNPA1 positively regulates lipid metabolism	[ [144] 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. Cell Commun. Signal. 2020 Oct 28; 18 (PMID: 33115498; PMCID: PMC7592379): 173https://doi.org/10.1186/s12964-020-00654-2 Crossref PubMed Scopus (13) Google Scholar ]
Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2)
Murine fat tissue	Ucp1	Suppresses translation	Adipose IGF2BP2 modulates nutrient and energy metabolism by reducing uncoupled oxygen consumption, glucose tolerance and insulin sensitivity	[ [73] 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. Cell Metabol. 2015 Apr 7; 21 (PMID: 25863250; PMCID: PMC4663978): 609-621https://doi.org/10.1016/j.cmet.2015.03.006 Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar ]
Murine hepatocytes	CPT-1A, PPARΑ	Increases stability and translation	Hepatic IGF2BP2 increases lipid oxidation.	[ [74] 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. J. Biol. Chem. 2019 Aug 2; 294 (Epub 2019 Jun 17. PMID: 31209109; PMCID: PMC6682725): 11944-11951https://doi.org/10.1074/jbc.RA119.008778 Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar ]
Murine adipocytes	HMGA1, IGF2, PPARα, ADIPOR1, ELOVL6, SCD	Increases translation and expression	Adipose IGF2BP2 modulates adipocyte differentiation and lipid metabolism	[ [145] 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. Sci. Transl. Med. 2018 Jun 20; 10 (PMID: 29925637; PMCID: PMC6620026)eaar5987https://doi.org/10.1126/scitranslmed.aar5987 Crossref Scopus (37) Google Scholar ]
Quaking (QKI)
Murine monocytes	CD36, LDLR, ABCG1, NR1H3, PPARG	Increases expression	Myeloid QKI impairs foam cell formation in monocytes and macrophages	[ [57] 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. Nat. Commun. 2016 Mar 31; 7 (PMID: 27029405; PMCID: PMC4821877)10846https://doi.org/10.1038/ncomms10846 Crossref PubMed Scopus (70) Google Scholar ]
Human monocytes	SRA	Reduces expression	Myeloid QKI reduces lipid uptake in monocytes to macrophage differentiation	[ [68] 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. Biochem. Biophys. Res. Commun. 2015 Aug 14; 464 (Epub 2015 Jun 6. PMID: 26056009): 1-6https://doi.org/10.1016/j.bbrc.2015.05.019 Crossref PubMed Scopus (12) Google Scholar ]
Src-Associated substrate in Mitosis of 68 kDa (Sam68)
Inguinal and epididymal white adipose tissue	Ucp1, Prdm16, Dio2, Cidea, Elovl3, Cidec, Cpt1b	Reduces expression	Adipose Sam68 suppresses fat tissue browning	[ [146] 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. J. Endocrinol. 2015 Jun; 225 (Epub 2015 May 1. PMID: 25934704; PMCID: PMC4482239): 181-189https://doi.org/10.1530/JOE-14-0727 Crossref PubMed Scopus (11) Google Scholar ]
Murine Preadipocyte and fat tissue	Rps6kb1	Alternative splicing	Adipose Sam68 modulates adipogenesis	[ [147] Song J. Richard S. Sam68 regulates S6K1 alternative splicing during adipogenesis. Mol. Cell Biol. 2015 Jun 1; 35 (Epub 2015 Mar 16. PMID: 25776557; PMCID: PMC4420930): 1926-1939https://doi.org/10.1128/MCB.01488-14 Crossref PubMed Scopus (23) Google Scholar ]
Murine Preadipocyte	mTOR	Alternative splicing	Adipose Sam68 induces adipogenesis and reduces energy expenditure in mice	[ [148] 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. Mol. Cell. 2012 Apr 27; 46 (Epub 2012 Mar 15. PMID: 22424772): 187-199https://doi.org/10.1016/j.molcel.2012.02.007 Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar ]
SUB1 homolog (SUB1)
Murine BMDM	Abcg1, Abca1	Reduces expression	Myeloid Sub1 upregulates cholesterol accumulation in macrophages	[ [142] 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. Adv. Sci. 2021 Oct; 8 (Epub 2021 Aug 10. PMID: 34378353; PMCID: PMC8498911)e2004162https://doi.org/10.1002/advs.202004162 Crossref Scopus (4) Google Scholar ]
Murine BMDM	Olr1, Irf1	Increases expression
Tristetraprolin (TTP)
Murine primary hepatocytes	FGF21	Reduces stability and expression	Hepatic TTP reduces insulin sensitivity and brown fat activation	[ [149] 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. JCI Insight. 2018 Jul 12; 3 (PMID: 29997282; PMCID: PMC6124529)e95948https://doi.org/10.1172/jci.insight.95948 Crossref PubMed Scopus (15) Google Scholar ]

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.

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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 [

[58]

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 [

[58]

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 [

[59]

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 [

[59]

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 [

[60]

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 [

61

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.

,

62

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.

,

63

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.

,

64

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 [

[65]

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 [

[3]

Libby P.
Buring J.E.
Badimon L.
Hansson G.K.
Deanfield J.
Bittencourt M.S.
Tokgözoğlu L.
Lewis E.F.

Atherosclerosis.

,

[66]

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 [

[67]

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 [

[68]

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 [

[69]

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 [

[70]

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 [

[71]

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 [

[72]

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.

,

[73]

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 [

[73]

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.

,

[74]

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 [

[75]

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 [

[76]

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.

,

[77]

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 [

[78]

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 studied	Target	Effect on target expression	Effect of tissue-specific RBP in smooth muscle cell regulation	Ref.
DEAD box protein 5 (DDX-5)
Murine VSMCs	Cyclin D1, PCNA	Decreases expression	SMC DDX-5 reduces proliferation, migration and vascular remodeling	[ [86] 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. Circ. Res. 2019 May 10; 124 (PMID: 30879402): e84-e100https://doi.org/10.1161/CIRCRESAHA.119.314062 Crossref PubMed Scopus (12) Google Scholar ]
Murine VSMCs	P27, GATA-6	Increases expression
Human antigen R (HuR)
Human aortic SMCs	SAT1, CDK2	Increases expression	HuR promotes SMC proliferation	[ [37] 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. J. Biol. Chem. 2005 Jun 17; 280 (Epub 2005 Apr 11. PMID: 15824116; PMCID: PMC1350862): 22819-22826https://doi.org/10.1074/jbc.M501106200 Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar ]
Rat aortic SMCs	sGCβ1	Increases stability and expression	SMC HuR enhances relaxation of rat aorta	[ [79] 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. Arterioscler. Thromb. Vasc. Biol. 2011 Mar; 31 (Epub 2010 Dec 16. PMID: 21164076): 567-573https://doi.org/10.1161/ATVBAHA.110.219725 Crossref PubMed Scopus (15) Google Scholar ]
Human aortic VSMCs	CRP, TNF-α, TLR4	Regulation of expression	SMC HuR increases inflammation and induces VSMC proliferation	[ [150] Liu Liang The anti-inflammatory effect of miR-16 through targeting C- reactive protein is regulated by HuR in vascular smooth muscle cells. Biochem. Biophys. Res. Commun. 2020; 528 (ISSN 0006-291X): 636-643https://doi.org/10.1016/j.bbrc.2020.05.104 Crossref PubMed Scopus (2) Google Scholar ]
Human aortic SMCs	TLR4	Increases stability and expression	SMC HuR is increased upon balloon-injury in rat aorta and aggravates TLR4 expression under LPS-stimulation	[ [151] 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. Arterioscler. Thromb. Vasc. Biol. 2006 Dec; 26 (Epub 2006 Sep 21. PMID: 16990552): 2622-2629https://doi.org/10.1161/01.ATV.0000246779.78003.cf Crossref PubMed Scopus (64) Google Scholar ]
Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1)
Murine VSMCs	IQGAP1	Reduces stability and expression	SMC hnRNPA1 reduces proliferation in neointima formation in wire-injured carotid arteries	[ [152] 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. Arterioscler. Thromb. Vasc. Biol. 2017 Nov; 37 (Epub 2017 Sep 14. Erratum in: Arterioscler Thromb Vasc Biol. 2020 Nov;40(11):e311. PMID: 28912364; PMCID: PMC5660626): 2182-2194https://doi.org/10.1161/ATVBAHA.117.310020 Crossref PubMed Scopus (34) Google Scholar ]
Murine ESC-derived VSMCs	Acta2, Tagin, SRF, MEF2c, Myocd	Increases expression	SMC hnRNPA1 increases VSMC differentiation from stem cells	[ [153] 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. Stem Cell. 2013 May; 31 (PMID: 23335105): 906-917https://doi.org/10.1002/stem.1324 Crossref PubMed Scopus (27) Google Scholar ]
Heterogeneous Nuclear Ribonucleoprotein A2/B1 (hnRNPA2B1)
Murine ESC-derived SMCs	SMαA, SM-MHC, SRF, Cbx3, MYOCD.	Increases expression	SMC hnRNPA2/B1 induces SMC differentiation from stem cells and arterial development	[ [154] 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. J. Biol. Chem. 2012 Jan 20; 287 (146) (Epub 2011 Dec 5. PMID: 22144681; PMCID: PMC3268446): 2896-2906https://doi.org/10.1074/jbc.M111.297028 Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar ]
VSMCs	hnRNPA2/B1	Reduces expression	SMC hnRNPA2/B1 promotes atherosclerotic VSMC proliferation	[ [155] 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. DNA Cell Biol. 2021 May; 40 (Epub 2021 Mar 30. PMID: 33781092): 652-661https://doi.org/10.1089/dna.2020.6451 Crossref PubMed Scopus (5) Google Scholar ]
Muscleblind Like Splicing Regulator 1 (MBNL1)
Human aortic VSMCs	Abi1	Alternative splicing	SMC MBNL1 induces macrophage-like phenotype differentiation of VSMC	[ [91] 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. Cell Prolif. 2021 May; 54 (Epub 2021 Mar 23. PMID: 33759281; PMCID: PMC8088461)e13023https://doi.org/10.1111/cpr.13023 Crossref Scopus (1) Google Scholar ]
Polypyrimidine tract binding proteins ½ (PTBP1/2)
Rat pulmonary artery SMCs	Dock7, Atp2b4, Dst, Pkm, Actn1, Tpm1, Itga7	Alternative splicing	SMC PTBP1/PTBP2 regulates alternative splicing during SMC de-differentiation	[ [85] 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. Nucleic Acids Res. 2016 Oct 14; 44 (Epub 2016 Jun 17. PMID: 27317697; PMCID: PMC5062968): 8933-8950https://doi.org/10.1093/nar/gkw560 Crossref PubMed Scopus (29) Google Scholar ]
Quaking (QKI)
Porcine SMCs	MYOCD	Alternative splicing	SMC QKI induces SMC differentiation to proliferative phenotype	[ [81] 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. Circ. Res. 2013 Oct 12; 113 (Epub 2013 Aug 20. PMID: 23963726): 1065-1075https://doi.org/10.1161/CIRCRESAHA.113.301302 Crossref PubMed Scopus (63) Google Scholar ]
Murine iPS-derived SMCs	HDAC7	Alternative splicing	iPS QKI induces SMC differentiation to contractile phenotype	[ [82] 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. J. Cell Sci. 2019 Aug 15; 132 (PMID: 31331967)jcs230276https://doi.org/10.1242/jcs.230276 Crossref PubMed Scopus (17) Google Scholar ]
Murine ESC-derived VSMCs	SMA, SM22, SM-MHC, MYOCD, SRF, MEF-2c	Reduces expression	QKI reduces VSMC transcriptional regulators during differentiation from stem cells	[ [156] 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. Oncotarget. 2017 Mar 21; 8 (PMID: 28186995; PMCID: PMC5386729): 19866-19878https://doi.org/10.18632/oncotarget.15189 Crossref PubMed Scopus (24) Google Scholar ]
Serine/arginine-rich splicing factor 1 (SRSF1)
Murine VSMC s	Δ133p53	Increases expression	SMC SRSF1 promotes neointima proliferation after wire-injured carotid artery	[ [87] 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. Nat. Commun. 2017 Aug 11; 8 (PMID: 28799539; PMCID: PMC5561544)16016https://doi.org/10.1038/ncomms16016 Crossref Scopus (44) Google Scholar ]
Human aortic SMCs	Δ133p53	Increases expression
Human aortic SMCs	NUB1	Increases stability and expression	SMC SRSF1 upregulates proliferation and migration of SMC	[ [88] 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. Atherosclerosis. 2022 Jan; 340 (Epub 2021 Nov 8. PMID: 34847450): 1-11https://doi.org/10.1016/j.atherosclerosis.2021.11.006 Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar ]
Transformer-2 protein homolog beta (Tra2β)
Rat aortic SMCs	MYPTI	Alternative splicing	SMC Tra2β induces VSMC diversification between slow and fast smooth muscle phenotype	[ [83] Shukla S. Fisher S.A. Tra2beta as a novel mediator of vascular smooth muscle diversification. Circ. Res. 2008 Aug 29; 103 (Epub 2008 Jul 31. PMID: 18669920; PMCID: PMC2737447): 485-492https://doi.org/10.1161/CIRCRESAHA.108.178384 Crossref PubMed Scopus (24) Google Scholar ]
Murine mesenteric artery SMCs	MYPTI	Alternative splicing	SMC Tra2β reduces vasorelaxation	[ [84] 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. Am. J. Physiol. Cell Physiol. 2015 Feb 15; 308 (Epub 2014 Nov 26. PMID: 25428883; PMCID: PMC4329427): C289-C296https://doi.org/10.1152/ajpcell.00304.2014 Crossref PubMed Scopus (12) Google Scholar ]
Rat VSMCs	RA301/Tra2β	Oxidative stress induces Tra2β expression	SMC Tra2β induces cell stress and VSMC proliferation through ERK signaling pathway	[ [157] 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. Am. J. Pathol. 2001 May; 158 (PMID: 11337366; PMCID: PMC1891943): 1685-1694https://doi.org/10.1016/s0002-9440(10)64124-7 Abstract Full Text Full Text PDF PubMed Google Scholar ]

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.

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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 [

[79]

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.

,

[80]

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 [

[37]

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 [

[37]

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) [

[37]

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.

,

[80]

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 [

[81]

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.

,

[82]

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 [

[81]

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.

,

[82]

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 [

[81]

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) [

[82]

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 [

[83]

Shukla S.
Fisher S.A.

Tra2beta as a novel mediator of vascular smooth muscle diversification.

,

[84]

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 [

[85]

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 [

[86]

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 [

[87]

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 [

[87]

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 [

[88]

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.

,

[89]

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 [

[90]

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 [

[91]

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) [

[92]

He C.
Klionsky D.J.

Regulation mechanisms and signaling pathways of autophagy.

]. HuR binds to and stabilizes the mRNAs of AMPKα1 and AMPKα2 [

[93]

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 [

[93]

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 [

[4]

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 [

[4]

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 [

[57]

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) [

[57]

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 [

[94]

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 [

[95]

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 [

[96]

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 [

[97]

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 [

[4]

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) [

[98]

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.

,

[99]

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 [

[100]

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 [

[101]

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.

,

[102]

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 [

[103]

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.

,

[104]

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 [

[63]

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) [

[42]

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 [

[46]

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 [

[103]

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.

,

[105]

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 [

[106]

Zernecke A.
Weber C.

Chemokines in atherosclerosis: proceedings resumed.

]. In macrophages and myeloid cells, TTP negatively regulates CXCL1 and CXCL2 mRNA [

[107]

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.

,

[108]

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 studied	Target	Effect on target expression	Effect of tissue-specific RBP in inflammation and oxidative stress	Ref.
AU-rich element RNA-binding protein 1 (AUF1)
Bovine aortic EC	VCAM-1	Increases stability and expression	EC AUF1 induces macrophage infiltration to the intima of atherosclerotic vessels	[ [45] 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. PLoS One. 2012; 7 (Epub 2012 Aug 10. Erratum in: PLoS One. 2012;7(8). doi: 10.1371/annotation/6f8adaaa-19d8-4187-9418-24a05ae77c8c. PMID: 22900050; PMCID: PMC3416774)e42808https://doi.org/10.1371/journal.pone.0042808 Crossref Scopus (11) Google Scholar ]
Murine BMDM	IL-10, IL-6, TNF-α	Decreases stability and expression	Myeloid AUF1 subcellular localization-reduces LPS-induced inflammatory response	[ [112] Yu H. Sun Y. Haycraft C. Palanisamy V. Kirkwood K.L. MKP-1 regulates cytokine mRNA stability through selectively modulation subcellular translocation of AUF1. Cytokine. 2011 Nov; 56 (Epub 2011 Jul 5. PMID: 21733716; PMCID: PMC3185122): 245-255https://doi.org/10.1016/j.cyto.2011.06.006 Crossref PubMed Scopus (39) Google Scholar ]
HUVECs	Neat1	Increased stability and expression	EC AUF1 positively regulates inflammation-activated endothelium in atherosclerotic vascular disease	[ [158] 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. J. Mol. Cell. Cardiol. 2021 Nov; 160 (Epub 2021 Jul 21. PMID: 34302813; PMCID: PMC8585018): 111-120https://doi.org/10.1016/j.yjmcc.2021.07.005 Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar ]
Human monocytes	IL-10, TAK1	Increases expression by activating IkappaB kinase complex and induces TAK1 mRNA translation	Myeloid AUF1 contributes to anti-inflammatory, LPS-induced IL-10 production and TAK1-mediated NFκB signaling	[ [159] 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. Mol. Cell Biol. 2011 Feb; 31 (Epub 2010 Dec 6. PMID: 21135123; PMCID: PMC3028643): 602-615https://doi.org/10.1128/MCB.00835-10 Crossref PubMed Scopus (38) Google Scholar ]
Cell Cycle Associated Protein 1 (CAPRIN1)
Murine monocytes,	STAT1	Increases stability and expression	Myeloid CAPRIN1 promotes IFN-γ innate immune responses in macrophages from mice infected with Listeria monocytogenes	[ [160] 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. Nat. Immunol. 2019 Dec; 20 (Epub 2019 Nov 18. Erratum in: Nat Immunol. 2020 Apr;21(4):477-478. PMID: 31740800): 1621-1630https://doi.org/10.1038/s41590-019-0542-7 Crossref PubMed Scopus (62) Google Scholar ]
Human kidney cells	STAT1	Increases stability and expression
Cold-inducible RNA-binding protein (CIRP)
Murine lung tissue	BiP, pIRE1α, sXBP1, CHOP, c-Casp-12, IL-6, IL-1β, MIP2, KC, MPO	Increases expression	Lung CIRBP1 increases ER stress-mediated apoptosis and inflammation in acute lung injury in a murine sepsis model	[ [161] 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. Sci. Rep. 2017 Jan 27; 7 (PMID: 28128330; PMCID: PMC5269663)41363https://doi.org/10.1038/srep41363 Crossref Scopus (51) Google Scholar ]
Human liver cells	TLR4, gp91, p47, Fis-1	Increases expression	Hepatic CIRBP1 induces oxidative stress and mitochondrial dysfunction in liver ischemia‐reperfusion injury	[ [162] 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. J. Cell Mol. Med. 2021 Dec; 25 (Epub 2021 Nov 16. PMID: 34786826; PMCID: PMC8650030): 11310-11321https://doi.org/10.1111/jcmm.17062 Crossref PubMed Scopus (4) Google Scholar ]
Human liver cells	UCP2, TFAM	Decreases expression
Murine liver tissue	IL-6, TNF-α	Increases expression.	Hepatic CIRBP1 and released CIRP from macrophages induces cytokine production attenuating organ damage in hemorrhage and sepsis	[ [163] 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. Nat. Med. 2013 Nov; 19 (Epub 2013 Oct 6. PMID: 24097189; PMCID: PMC3826915): 1489-1495https://doi.org/10.1038/nm.3368 Crossref PubMed Scopus (238) Google Scholar ]
Murine macrophages	IL-6R	Secreted CRP1 binds to IL-6R initiating downstream signaling	Myeloid CIRBP1 promotes macrophage endotoxin tolerance and M2 polarization in LPS-induced sepsis	[ [164] 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. JCI Insight. 2020 Mar 12; 5 (PMID: 32027619; PMCID: PMC7141386)e133715https://doi.org/10.1172/jci.insight.133715 Crossref Scopus (19) Google Scholar ]
Human antigen R (HuR)
HUVECs	VCAM1, ICAM1	Increases expression	Shear stress-induced EC HuR. HuR increases adhesion molecule expression and monocyte binding to LPS-response	[ [35] 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. Proc. Natl. Acad. Sci. U. S. A. 2010 Apr 13; 107 (Epub 2010 Mar 29. PMID: 20351266; PMCID: PMC2872448): 6858-6863https://doi.org/10.1073/pnas.1000444107 Crossref PubMed Scopus (72) Google Scholar ]
Murine and human EC	CD62E, CTSS	Increases stability and expression	EC HuR increases EC activation and monocyte recruitment	[ [36] 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. Circulation. 2019 Jan 2; 139 (PMID: 29970364): 101-114https://doi.org/10.1161/CIRCULATIONAHA.118.034757 Crossref PubMed Scopus (64) Google Scholar ]
Murine spleen, aorta, BMDM and VSMCs	HuR	IL-19 decreases HuR stability and expression	IL-19 reduces atherosclerotic plaque area by reducing HuR and inflammatory gene expression	[ [38] 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). Arterioscler. Thromb. Vasc. Biol. 2018 Jun; 38 (Epub 2018 Apr 19. PMID: 29674474; PMCID: PMC5970062): 1297-1308https://doi.org/10.1161/ATVBAHA.118.310929 Crossref PubMed Scopus (22) Google Scholar ]
Murine embryonic fibroblast	IL-β, TNF-α, TGF-β, MMP9, COL1A1, COL1A2, COL3A1, αSMA	Increases expression	Fibroblast HuR induces inflammation and fibrogenesis	[ [113] 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. Faseb. J. 2020 Feb; 34 (Epub 2019 Dec 16. PMID: 31907992; PMCID: PMC8286699): 2238-2251https://doi.org/10.1096/fj.201901995R Crossref PubMed Scopus (22) Google Scholar ]
Murine BMDM and aorta	HuR	lncRNA MAARS retains HuR in the nucleus	Myeloid HuR induces efferocytosis	[ [165] 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. Nat. Commun. 2020 Dec 1; 11 (PMID: 33262333; PMCID: PMC7708640): 6135https://doi.org/10.1038/s41467-020-19664-2 Crossref PubMed Scopus (63) Google Scholar ]
Human gingival EC	IL-6	Increases stability and expression	EC HuR increases inflammatory responses in periodontitis	[ [166] 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. Clin. Exp. Immunol. June 2018; 192: 325-336https://doi.org/10.1111/cei.13110 Crossref PubMed Scopus (18) Google Scholar ]
Murine BMDM	Mcf2	Increases expression	Myeloid HuR increases Dab1-mediated Rac1 activation and efferocytosis	[ [167] 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. Cell Metabol. 2020 Mar 3; 31 (Epub 2020 Jan 30. PMID: 32004476; PMCID: PMC7173557): 518-533.e10https://doi.org/10.1016/j.cmet.2020.01.001 Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar ]
Murine BMDM	TNF-α	Reduces stability of mRNA by recruiting destabilizing RBP	Myeloid HuR reduces inflammation and hepatic cell damage	[ [168] Katsanou V. Papadaki O. Milatos S. Blackshear P.J. Anderson P. Kollias G. Kontoyiannis D.L. HuR as a negative posttranscriptional modulator in inflammation. Mol. Cell. 2005 Sep 16; 19 (PMID: 16168373): 777-789https://doi.org/10.1016/j.molcel.2005.08.007 Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar ]
Murine naïve CD4⁺ T cells	IL-6Rα, cMaf	Increases stability and expression	Myeloid HuR induces Th17 differentiation and IL-22 production	[ [169] 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. J. Immunol. Res. 2021 Aug 4; (2021)9937243https://doi.org/10.1155/2021/9937243 Crossref Scopus (3) Google Scholar ]
Murine ECs	14-3-3ζ	Increases translation and expression	EC HuR induces intestine wound healing and cell migration	[ [170] 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. Phys. Rep. 2016 Jul; 4 (PMID: 27401462; PMCID: PMC4945840)e12858https://doi.org/10.14814/phy2.12858 Crossref Scopus (5) Google Scholar ]
Fragile-X mental retardation autosomal 1 (FXR1)
Human VSMC	ICAM-1, IL-1β, MCP-1, TNF-α, HuR	Decreases stability and expression	SMC FXR1 reduces inflammation and VSMC proliferation in vascular atherosclerotic disease	[ [61] 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. Cell Rep. 2018 Jul 31; 24 (PMID: 30067974): 1176-1189https://doi.org/10.1016/j.celrep.2018.07.002 Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar ]
Human Monocytes	IL-1β, CCL2	Increases expression	Myeloid FXR1 induces monocyte cell migration.	[ [63] 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. Cell Cycle. 2016 Jul 17; 15 (Epub 2016 May 26. PMID: 27229378): 1874-1882https://doi.org/10.1080/15384101.2016.1189040 Crossref PubMed Scopus (12) Google Scholar ]
Heterogeneous nuclear ribonucleoprotein K (hnRNPK1)
Human Monocytes	IP-10	Increases stability and expression	Myeloid hnRNPK1 increases monocyte activation	[ [171] Natarajan K. Sundaramoorthy A. Shanmugam N. HnRNPK and lysine specific histone demethylase-1 regulates IP-10 mRNA stability in monocytes. Eur. J. Pharmacol. 2022 Apr 5; 920 (Epub 2021 Dec 13. PMID: 34914972)174683https://doi.org/10.1016/j.ejphar.2021.174683 Crossref PubMed Scopus (1) Google Scholar ]
Human EC	UCP2	Suppresses translation	EC hnRNPK1 reduces ROS production	[ [172] 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. Cell. Signal. 2014 Jul; 26 (Epub 2014 Mar 15. PMID: 24642125; PMCID: PMC4039131): 1379-1384https://doi.org/10.1016/j.cellsig.2014.03.005 Crossref PubMed Scopus (12) Google Scholar ]
Quaking (QKI)
Murine monocytes/macrophage	NRF2, HMOX1, NQO1, GCLC	Increases expression	Myeloid QKI reduces ROS production in macrophages in chronic inflammatory disease	[ [173] 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. Cell Death Dis. 2021 Mar 23; 7 (PMID: 33758177; PMCID: PMC7988119): 58https://doi.org/10.1038/s41420-021-00444-w Crossref Scopus (3) Google Scholar ]
Murine monocytes/macrophage	NOX2, p22, Keap1	Reduces expression
SUB1 homolog (SUB1)
Murine macrophages	TNF-α, IL-β, CCL2, NOS2	Increases expression	Myeloid Sub1 induces macrophage infiltration and enhances M1 macrophage phenotype in murine atherosclerosis models	[ [150] Liu Liang The anti-inflammatory effect of miR-16 through targeting C- reactive protein is regulated by HuR in vascular smooth muscle cells. Biochem. Biophys. Res. Commun. 2020; 528 (ISSN 0006-291X): 636-643https://doi.org/10.1016/j.bbrc.2020.05.104 Crossref PubMed Scopus (2) Google Scholar ]
Cytotoxic granule-associated RNA-binding protein (TIA1)
Murine peritoneal macrophages	TNF-α	Reduces translation and expression	Myeloid TIA1 attenuates LPS-induced endotoxin shock	[ [174] 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. EMBO J. 2000 Aug 1; 19 (PMID: 10921895; PMCID: PMC306595): 4154-4163https://doi.org/10.1093/emboj/19.15.4154 Crossref PubMed Scopus (417) Google Scholar ]
Murine embryonic fibroblasts and colorectal cells	Cox-2	Reduces translation and expression	Myeloid TIA1 reduces prostaglandin expression	[ [175] 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. J. Exp. Med. 2003 Aug 4; 198 (Epub 2003 Jul 28. PMID: 12885872; PMCID: PMC2194089): 475-481https://doi.org/10.1084/jem.20030616 Crossref PubMed Scopus (164) Google Scholar ]
Y-box protein 1 (YB-1)
Human macrophages	CD36	Promotes decay and reduces expression independent of transcription	Myeloid YB-1 reduces lipid deposition in LDL-stimulated macrophages	[ [176] 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. Free Radic. Biol. Med. 2019 Sep; 141 (Epub 2019 May 31. PMID: 31153975): 10-20https://doi.org/10.1016/j.freeradbiomed.2019.05.032 Crossref PubMed Scopus (9) Google Scholar ]
Human T lymphocytes, rat mesangial cells	IL-10	Increases expression	Renal YB1 reduces renal damage and monocyte infiltration after ischemia-reperfusion injury	[ [177] 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. J. Cell Mol. Med. 2017 Dec; 21 (Epub 2017 Jun 30. PMID: 28664613; PMCID: PMC5706504): 3494-3505https://doi.org/10.1111/jcmm.13260 Crossref PubMed Scopus (16) Google Scholar ]
Tristetraprolin (TTP)
Human monocytes	TNF-α, p21, EGR1, FOS	Increases binding and reduces expression	Myeloid TTP reduces macrophage transcriptional regulators in atherosclerosis	[ [95] 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. Circ. Res. 2006 May 26; 98 (Epub 2006 Apr 13. PMID: 16614304): 1282-1289https://doi.org/10.1161/01.RES.0000222284.48288.28 Crossref PubMed Scopus (33) Google Scholar ]
Murine BMDM	IL-1β, CXCL2	Reduces expression	Myeloid TTP reduces immune cell infiltration in murine models of chronic inflammatory disease	[ [101] 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. Proc. Natl. Acad. Sci. U. S. A. 2016 Feb 16; 113 (Epub 2016 Feb 1. PMID: 26831084; PMCID: PMC4763790): 1865-1870https://doi.org/10.1073/pnas.1519906113 Crossref PubMed Scopus (63) Google Scholar ]
Murine peritoneal macrophages and liver tissue	TNF-α, SAA1, CCR2	Reduces expression	Myeloid and hepatic TTP reduces inflammation in LPS-stimulates macrophages and mitochondrial reactive oxygen species production	[ [102] 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. Redox Biol. 2020 Oct; 37 (Epub 2020 Jun 17. PMID: 32591281; PMCID: PMC7767740)101609https://doi.org/10.1016/j.redox.2020.101609 Crossref Scopus (8) Google Scholar ]
Murine peritoneal macrophages and liver tissue	SREBF1	Increases expression
Human hepatic cells	CCL2, CCL5	Reduces stability through m⁶A-mediated methylation	Hepatic TTP reduces macrophage infiltration in murine acute liver failure model	[ [103] 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. JCI Insight. 2021 Dec 8; 6 (PMID: 34877932; PMCID: PMC8675193)e149276https://doi.org/10.1172/jci.insight.149276 Crossref Scopus (4) Google Scholar ]
Human arterial EC and monocytes	MCP-1, IL-6, NF-κB	Increases binding and reduces expression	EC and myeloid TTP reduces EC inflammation and atherosclerotic lesions	[ [104] 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. Arterioscler. Thromb. Vasc. Biol. 2013 Jun; 33 (Epub 2013 Apr 4. PMID: 23559629; PMCID: PMC3844532): 1212-1220https://doi.org/10.1161/ATVBAHA.113.301496 Crossref PubMed Scopus (39) Google Scholar ]
Murine BMDM	TNF-α, CXCL10, GDF15, Dusp1, Ier3, Tnfaip3	Reduces stability, translation, and expression	Myeloid TTP reduces inflammatory gene expression and modulates apoptosis in LPS-stimulated macrophages	[ [105] 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. Nucleic Acids Res. 2016 Sep 6; 44 (Epub 2016 May 24. PMID: 27220464; PMCID: PMC5009735): 7418-7440https://doi.org/10.1093/nar/gkw474 Crossref PubMed Scopus (101) Google Scholar ]
Murine BMDM	CXCL1, IL-10, TNF-α	Reduces expression by degradation	Myeloid TTP reduces inflammation in LPS-stimulated macrophages	[ [107] 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. J. Immunol. 2015 Jul 1; 195 (Epub 2015 May 22. PMID: 26002976; PMCID: PMC4472942): 265-276https://doi.org/10.4049/jimmunol.1402826 Crossref PubMed Scopus (58) Google Scholar ]
Murine BMDM	IL-1α, TNF-α	Reduces stability and expression	IL-10-mediated myeloid TTP expression reduces inflammation in LPS-stimulated macrophages	[ [110] 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. J. Immunol. 2009 Jul 15; 183 (Epub 2009 Jun 19. PMID: 19542371; PMCID: PMC2755621): 1197-1206https://doi.org/10.4049/jimmunol.0803883 Crossref PubMed Scopus (86) Google Scholar ]
Murine peritoneal and blood macrophages	CD36	Increases CD36 mRNA decay by binding to the 3′UTR	Myeloid TTP reduces oxLDL uptake, intracellular cholesterol content and foam-cell formation	[ [178] 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. Cardiovasc. Res. 2014 Feb 1; 101 (Epub 2013 Nov 18. PMID: 24253523): 297-305https://doi.org/10.1093/cvr/cvt254 Crossref PubMed Scopus (25) Google Scholar ]
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