Advertisement

Nuclear receptors in abdominal aortic aneurysms

      Highlights

      • Abdominal aortic aneurysms are treated surgically since there is no pharmacotherapy.
      • They share several pathophysiological mechanisms with atherosclerosis.
      • Nuclear receptors often have similar roles in both pathologies.
      • Several nuclear receptors are attractive therapeutic targets.

      Abstract

      Abdominal aortic aneurysms (AAA) pose a considerable health burden and at present are only managed surgically since there is no proven pharmacotherapy that will retard their expansion or reduce the incidence of fatal rupture. This pathology shares several pathophysiological mechanisms with atherosclerosis, such as macrophage infiltration, inflammation, and degradation of extracellular matrix. Therefore, therapeutic targets proven effective in the treatment of atherosclerosis could also be considered for treatment of AAA. Different members of the nuclear receptor (NR) superfamily have been extensively studied as potential targets in the treatment of cardiovascular disease (CVD) and therefore might also be suited for AAA treatment. In this context, this review summarizes the role of different NRs in CVD, mostly atherosclerosis, and discusses in detail the current knowledge of their implications in AAA. From this overview it becomes apparent that NRs that were attributed a beneficial or adverse role in CVD have similar roles in AAA. Together, this overview provides compelling evidence to consider several NRs as attractive targets for future treatment of AAA.

      Graphical abstract

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Jones G.T.
        • Tromp G.
        • Kuivaniemi H.
        • et al.
        Meta-analysis of genome-wide association studies for abdominal aortic aneurysm identifies four new disease-specific risk loci.
        Circ. Res. 2017; 120: 341-353
        • Moll F.L.
        • Powell J.T.
        • Fraedrich G.
        • et al.
        Management of abdominal aortic aneurysms clinical practice guidelines of the European society for vascular surgery.
        Eur. J. Vasc. Endovasc. Surg. 2011; 41: S1-S58
        • Nienaber C.A.
        • Clough R.E.
        Management of acute aortic dissection.
        Lancet. 2015; 385: 800-811
        • Sakalihasan N.
        • Michel J.B.
        • Katsargyris A.
        • et al.
        Abdominal aortic aneurysms.
        Nat Rev Dis Primers. 2018; 4: 34
        • Brewster D.C.
        • Cronenwett J.L.
        • Hallett Jr., J.W.
        • et al.
        Guidelines for the treatment of abdominal aortic aneurysms. Report of a subcommittee of the joint council of the American association for vascular surgery and society for vascular surgery.
        J. Vasc. Surg. 2003; 37: 1106-1117
        • Anidjar S.
        • Salzmann J.L.
        • Gentric D.
        • et al.
        Elastase-induced experimental aneurysms in rats.
        Circulation. 1990; 82: 973-981
        • Dwivedi A.J.
        • Roy-Chaudhury P.
        • Peden E.K.
        • et al.
        Application of human type I pancreatic elastase (PRT-201) to the venous anastomosis of arteriovenous grafts in patients with chronic kidney disease.
        J. Vasc. Access. 2014; 15: 376-384
        • Dobrin P.B.
        • Baker W.H.
        • Gley W.C.
        Elastolytic and collagenolytic studies of arteries. Implications for the mechanical properties of aneurysms.
        Arch. Surg. 1984; 119: 405-409
        • Lareyre F.
        • Clement M.
        • Raffort J.
        • et al.
        TGFbeta (transforming growth factor-beta) blockade induces a human-like disease in a nondissecting mouse model of abdominal aortic aneurysm.
        Arterioscler. Thromb. Vasc. Biol. 2017; 37: 2171-2181
        • Lysgaard Poulsen J.
        • Stubbe J.
        • Lindholt J.S.
        Animal models used to explore abdominal aortic aneurysms: a systematic review.
        Eur. J. Vasc. Endovasc. Surg. 2016; 52: 487-499
        • Yamanouchi D.
        • Morgan S.
        • Stair C.
        • et al.
        Accelerated aneurysmal dilation associated with apoptosis and inflammation in a newly developed calcium phosphate rodent abdominal aortic aneurysm model.
        J. Vasc. Surg. 2012; 56: 455-461
        • Saraff K.
        • Babamusta F.
        • Cassis L.A.
        • et al.
        Aortic dissection precedes formation of aneurysms and atherosclerosis in angiotensin II-infused, apolipoprotein E-deficient mice.
        Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1621-1626
        • Trachet B.
        • Aslanidou L.
        • Piersigilli A.
        • et al.
        Angiotensin II infusion into ApoE-/- mice: a model for aortic dissection rather than abdominal aortic aneurysm?.
        Cardiovasc. Res. 2017; 113: 1230-1242
        • McEwan I.J.
        The nuclear receptor superfamily at thirty.
        Methods Mol. Biol. 2016; 1443: 3-9
        • Kurakula K.
        • Hamers A.A.
        • de Waard V.
        • et al.
        Nuclear Receptors in atherosclerosis: a superfamily with many 'Goodfellas'.
        Mol. Cell. Endocrinol. 2013; 368: 71-84
        • Bishop-Bailey D.
        Nuclear receptors in vascular biology.
        Curr. Atherosclerosis Rep. 2015; 17: 507
        • Ma Z.
        • Deng C.
        • Hu W.
        • et al.
        Liver X receptors and their agonists: targeting for cholesterol homeostasis and cardiovascular diseases.
        Curr. Issues Mol. Biol. 2017; 22: 41-64
        • Han L.
        • Shen W.J.
        • Bittner S.
        • et al.
        PPARs: regulators of metabolism and as therapeutic targets in cardiovascular disease. Part I: PPAR-alpha.
        Future Cardiol. 2017; 13: 259-278
        • Han L.
        • Shen W.J.
        • Bittner S.
        • et al.
        PPARs: regulators of metabolism and as therapeutic targets in cardiovascular disease. Part II: PPAR-beta/delta and PPAR-gamma.
        Future Cardiol. 2017; 13: 279-296
        • Norman P.E.
        • Powell J.T.
        Vitamin D and cardiovascular disease.
        Circ. Res. 2014; 114: 379-393
        • Iorga A.
        • Cunningham C.M.
        • Moazeni S.
        • et al.
        The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy.
        Biol. Sex Differ. 2017; 8: 33
        • Takov K.
        • Wu J.
        • Denvir M.A.
        • et al.
        The role of androgen receptors in atherosclerosis.
        Mol. Cell. Endocrinol. 2018; 465: 82-91
        • DuPont J.J.
        • Jaffe I.Z.
        30 years OF the mineralocorticoid receptor: the role of the mineralocorticoid receptor in the vasculature.
        J. Endocrinol. 2017; 234: T67-T82
        • Mirza A.Z.
        • Althagafi I.I.
        • Shamshad H.
        Role of PPAR receptor in different diseases and their ligands: physiological importance and clinical implications.
        Eur. J. Med. Chem. 2019; 166: 502-513
        • Jones D.
        • Boudes P.F.
        • Swain M.G.
        • et al.
        Seladelpar (MBX-8025), a selective PPAR-delta agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study.
        Lancet Gastroenterol Hepatol. 2017; 2: 716-726
        • Khuchua Z.
        • Glukhov A.I.
        • Strauss A.W.
        • et al.
        Elucidating the beneficial role of PPAR agonists in cardiac diseases.
        Int. J. Mol. Sci. 2018; 19
        • Abushouk A.I.
        • El-Husseny M.W.A.
        • Bahbah E.I.
        • et al.
        Peroxisome proliferator-activated receptors as therapeutic targets for heart failure.
        Biomed. Pharmacother. 2017; 95: 692-700
        • Boese A.C.
        • Kim S.C.
        • Yin K.J.
        • et al.
        Sex differences in vascular physiology and pathophysiology: estrogen and androgen signaling in health and disease.
        Am. J. Physiol. Heart Circ. Physiol. 2017; 313: H524-H545
        • Chistiakov D.A.
        • Myasoedova V.A.
        • Melnichenko A.A.
        • et al.
        Role of androgens in cardiovascular pathology.
        Vasc. Health Risk Manag. 2018; 14: 283-290
        • Nishiyama A.
        Pathophysiological mechanisms of mineralocorticoid receptor-dependent cardiovascular and chronic kidney disease.
        Hypertens. Res. 2019; 42: 293-300
        • Cannavo A.
        • Bencivenga L.
        • Liccardo D.
        • et al.
        Aldosterone and mineralocorticoid receptor system in cardiovascular physiology and pathophysiology.
        Oxid. Med. Cell. Longev. 2018; 2018: 1204598
        • Krezel W.
        • Ruhl R.
        • de Lera A.R.
        Alternative retinoid X receptor (RXR) ligands.
        Mol. Cell. Endocrinol. 2019; 491: 110436
        • Nohara A.
        • Kobayashi J.
        • Mabuchi H.
        Retinoid X receptor heterodimer variants and cardiovascular risk factors.
        J. Atherosclerosis Thromb. 2009; 16: 303-318
        • Pilz S.
        • Verheyen N.
        • Grubler M.R.
        • et al.
        Vitamin D and cardiovascular disease prevention.
        Nat. Rev. Cardiol. 2016; 13: 404-417
        • Jamali N.
        • Sorenson C.M.
        • Sheibani N.
        Vitamin D and regulation of vascular cell function.
        Am. J. Physiol. Heart Circ. Physiol. 2018; 314: H753-H765
        • Rasheed A.
        • Cummins C.L.
        Beyond the foam cell: the role of LXRs in preventing atherogenesis.
        Int. J. Mol. Sci. 2018; 19
        • Cannon M.V.
        • van Gilst W.H.
        • de Boer R.A.
        Emerging role of liver X receptors in cardiac pathophysiology and heart failure.
        Basic Res. Cardiol. 2016; 111: 3
        • van Tiel C.M.
        • de Vries C.J.
        NR4All in the vessel wall.
        J. Steroid Biochem. Mol. Biol. 2012; 130: 186-193
        • Rodriguez-Calvo R.
        • Tajes M.
        • Vazquez-Carrera M.
        The NR4A subfamily of nuclear receptors: potential new therapeutic targets for the treatment of inflammatory diseases.
        Expert Opin. Ther. Targets. 2017; 21: 291-304
        • Chao L.C.
        • Soto E.
        • Hong C.
        • et al.
        Bone marrow NR4A expression is not a dominant factor in the development of atherosclerosis or macrophage polarization in mice.
        J. Lipid Res. 2013; 54: 806-815
        • Qing H.
        • Liu Y.
        • Zhao Y.
        • et al.
        Deficiency of the NR4A orphan nuclear receptor NOR1 in hematopoietic stem cells accelerates atherosclerosis.
        Stem Cell. 2014; 32: 2419-2429
        • Golledge J.
        • Cullen B.
        • Rush C.
        • et al.
        Peroxisome proliferator-activated receptor ligands reduce aortic dilatation in a mouse model of aortic aneurysm.
        Atherosclerosis. 2010; 210: 51-56
        • Krishna S.M.
        • Seto S.W.
        • Moxon J.V.
        • et al.
        Fenofibrate increases high-density lipoprotein and sphingosine 1 phosphate concentrations limiting abdominal aortic aneurysm progression in a mouse model.
        Am. J. Pathol. 2012; 181: 706-718
        • Rowbotham S.E.
        • Krishna S.M.
        • Moran C.S.
        • et al.
        Fenofibrate and telmisartan in the management of abdominal aortic aneurysm.
        Curr. Drug Targets. 2018; 19: 1241-1246
        • Pinchbeck J.L.
        • Moxon J.V.
        • Rowbotham S.E.
        • et al.
        Randomized placebo-controlled trial assessing the effect of 24-week fenofibrate therapy on circulating markers of abdominal aortic aneurysm: outcomes from the FAME -2 trial.
        J Am. Heart Assoc. 2018; 7e009866
        • Rowbotham S.E.
        • Cavaye D.
        • Jaeggi R.
        • et al.
        Fenofibrate in the management of AbdoMinal aortic anEurysm (FAME): study protocol for a randomised controlled trial.
        Trials. 2017; 18: 1
        • Hwang J.S.
        • Kim H.J.
        • Kim G.
        • et al.
        PPARdelta reduces abdominal aortic aneurysm formation in angiotensin II-infused apolipoprotein E-deficient mice by regulating extracellular matrix homeostasis and inflammatory responses.
        Int. J. Cardiol. 2014; 174: 43-50
        • Jones A.
        • Deb R.
        • Torsney E.
        • et al.
        Rosiglitazone reduces the development and rupture of experimental aortic aneurysms.
        Circulation. 2009; 119: 3125-3132
        • Cai Z.
        • Zhao G.
        • Yan J.
        • et al.
        CYP2J2 overexpression increases EETs and protects against angiotensin II-induced abdominal aortic aneurysm in mice.
        J. Lipid Res. 2013; 54: 1448-1456
        • Wang W.D.
        • Sun R.
        • Chen Y.X.
        PPARgamma agonist rosiglitazone alters the temporal and spatial distribution of inflammation during abdominal aortic aneurysm formation.
        Mol. Med. Rep. 2018; 18: 3421-3428
        • Motoki T.
        • Kurobe H.
        • Hirata Y.
        • et al.
        PPAR-gamma agonist attenuates inflammation in aortic aneurysm patients.
        Gen. Thorac. Cardiovasc. Surg. 2015; 63: 565-571
        • Moran C.S.
        • Clancy P.
        • Biros E.
        • et al.
        Association of PPARgamma allelic variation, osteoprotegerin and abdominal aortic aneurysm.
        Clin. Endocrinol. 2010; 72: 128-132
        • Hamblin M.
        • Chang L.
        • Zhang H.
        • et al.
        Vascular smooth muscle cell peroxisome proliferator-activated receptor-gamma deletion promotes abdominal aortic aneurysms.
        J. Vasc. Surg. 2010; 52: 984-993
        • Tai H.C.
        • Tsai P.J.
        • Chen J.Y.
        • et al.
        Peroxisome proliferator-activated receptor gamma level contributes to structural integrity and component production of elastic fibers in the aorta.
        Hypertension. 2016; 67: 1298-1308
        • Park J.G.
        • Mok J.S.
        • Han Y.I.
        • et al.
        Connectivity mapping of angiotensin-PPAR interactions involved in the amelioration of non-alcoholic steatohepatitis by Telmisartan.
        Sci. Rep. 2019; 9: 4003
        • Singh K.
        • Bonaa K.H.
        • Jacobsen B.K.
        • et al.
        Prevalence of and risk factors for abdominal aortic aneurysms in a population-based study : the Tromso Study.
        Am. J. Epidemiol. 2001; 154: 236-244
        • Forbes T.L.
        • Lawlor D.K.
        • DeRose G.
        • et al.
        Gender differences in relative dilatation of abdominal aortic aneurysms.
        Ann. Vasc. Surg. 2006; 20: 564-568
        • Mofidi R.
        • Goldie V.J.
        • Kelman J.
        • et al.
        Influence of sex on expansion rate of abdominal aortic aneurysms.
        Br. J. Surg. 2007; 94: 310-314
        • Tong J.
        • Schriefl A.J.
        • Cohnert T.
        • et al.
        Gender differences in biomechanical properties, thrombus age, mass fraction and clinical factors of abdominal aortic aneurysms.
        Eur. J. Vasc. Endovasc. Surg. 2013; 45: 364-372
        • Tomee S.M.
        • Lijftogt N.
        • Vahl A.
        • et al.
        A registry-based rationale for discrete intervention thresholds for open and endovascular elective abdominal aortic aneurysm repair in female patients.
        J. Vasc. Surg. 2018; 67: 735-739
        • Egorova N.N.
        • Vouyouka A.G.
        • McKinsey J.F.
        • et al.
        Effect of gender on long-term survival after abdominal aortic aneurysm repair based on results from the Medicare national database.
        J. Vasc. Surg. 2011; 54 (e16; discussion 11-12): 1-12
        • Ailawadi G.
        • Eliason J.L.
        • Roelofs K.J.
        • et al.
        Gender differences in experimental aortic aneurysm formation.
        Arterioscler. Thromb. Vasc. Biol. 2004; 24: 2116-2122
        • Daugherty A.
        • Manning M.W.
        • Cassis L.A.
        Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice.
        J. Clin. Invest. 2000; 105: 1605-1612
        • Martin-McNulty B.
        • Tham D.M.
        • da Cunha V.
        • et al.
        17 Beta-estradiol attenuates development of angiotensin II-induced aortic abdominal aneurysm in apolipoprotein E-deficient mice.
        Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1627-1632
        • Henriques T.A.
        • Huang J.
        • D'Souza S.S.
        • et al.
        Orchidectomy, but not ovariectomy, regulates angiotensin II-induced vascular diseases in apolipoprotein E-deficient mice.
        Endocrinology. 2004; 145: 3866-3872
        • Villard C.
        • Eriksson P.
        • Kronqvist M.
        • et al.
        Differential expression of sex hormone receptors in abdominal aortic aneurysms.
        Maturitas. 2017; 96: 39-44
        • Laser A.
        • Ghosh A.
        • Roelofs K.
        • et al.
        Increased estrogen receptor alpha in experimental aortic aneurysms in females compared with males.
        J. Surg. Res. 2014; 186: 467-474
        • Grigoryants V.
        • Hannawa K.K.
        • Pearce C.G.
        • et al.
        Tamoxifen up-regulates catalase production, inhibits vessel wall neutrophil infiltration, and attenuates development of experimental abdominal aortic aneurysms.
        J. Vasc. Surg. 2005; 41: 108-114
        • Davis J.P.
        • Salmon M.
        • Pope N.H.
        • et al.
        Pharmacologic blockade and genetic deletion of androgen receptor attenuates aortic aneurysm formation.
        J. Vasc. Surg. 2016; 63: 1602-1612 e1602
        • Henriques T.
        • Zhang X.
        • Yiannikouris F.B.
        • et al.
        Androgen increases AT1a receptor expression in abdominal aortas to promote angiotensin II-induced AAAs in apolipoprotein E-deficient mice.
        Arterioscler. Thromb. Vasc. Biol. 2008; 28: 1251-1256
        • Huang C.K.
        • Luo J.
        • Lai K.P.
        • et al.
        Androgen receptor promotes abdominal aortic aneurysm development via modulating inflammatory interleukin-1alpha and transforming growth factor-beta1 expression.
        Hypertension. 2015; 66: 881-891
        • Zavatta G.
        • Di Dalmazi G.
        • Pizzi C.
        • et al.
        Larger ascending aorta in primary aldosteronism: a 3-year prospective evaluation of adrenalectomy vs. medical treatment.
        Endocrine. 2019; 63: 470-475
        • Lenk G.M.
        • Tromp G.
        • Weinsheimer S.
        • et al.
        Whole genome expression profiling reveals a significant role for immune function in human abdominal aortic aneurysms.
        BMC Genom. 2007; 8: 237
        • Thompson A.
        • Cooper J.A.
        • Fabricius M.
        • et al.
        An analysis of drug modulation of abdominal aortic aneurysm growth through 25 years of surveillance.
        J. Vasc. Surg. 2010; 52: 55-61 e52
        • Kurobe H.
        • Hirata Y.
        • Matsuoka Y.
        • et al.
        Protective effects of selective mineralocorticoid receptor antagonist against aortic aneurysm progression in a novel murine model.
        J. Surg. Res. 2013; 185: 455-462
        • Liu S.
        • Xie Z.
        • Daugherty A.
        • et al.
        Mineralocorticoid receptor agonists induce mouse aortic aneurysm formation and rupture in the presence of high salt.
        Arterioscler. Thromb. Vasc. Biol. 2013; 33: 1568-1579
        • Cassis L.A.
        • Helton M.J.
        • Howatt D.A.
        • et al.
        Aldosterone does not mediate angiotensin II-induced atherosclerosis and abdominal aortic aneurysms.
        Br. J. Pharmacol. 2005; 144: 443-448
        • Escudero P.
        • Navarro A.
        • Ferrando C.
        • et al.
        Combined treatment with bexarotene and rosuvastatin reduces angiotensin-II-induced abdominal aortic aneurysm in apoE(-/-) mice and angiogenesis.
        Br. J. Pharmacol. 2015; 172: 2946-2960
        • Yen W.C.
        • Lamph W.W.
        The selective retinoid X receptor agonist bexarotene (LGD1069, Targretin) prevents and overcomes multidrug resistance in advanced breast carcinoma.
        Mol. Canc. Therapeut. 2005; 4: 824-834
        • Takeda K.
        • Ichiki T.
        • Funakoshi Y.
        • et al.
        Downregulation of angiotensin II type 1 receptor by all-trans retinoic acid in vascular smooth muscle cells.
        Hypertension. 2000; 35: 297-302
        • Nieuwland A.J.
        • Kokje V.B.
        • Koning O.H.
        • et al.
        Activation of the vitamin D receptor selectively interferes with calcineurin-mediated inflammation: a clinical evaluation in the abdominal aortic aneurysm.
        Lab. Invest. 2016; 96: 784-790
        • Martorell S.
        • Hueso L.
        • Gonzalez-Navarro H.
        • et al.
        Vitamin D receptor activation reduces angiotensin-II-induced dissecting abdominal aortic aneurysm in apolipoprotein E-knockout mice.
        Arterioscler. Thromb. Vasc. Biol. 2016; 36: 1587-1597
        • Parikh M.
        • Patel K.
        • Soni S.
        • et al.
        Liver X receptor: a cardinal target for atherosclerosis and beyond.
        J. Atherosclerosis Thromb. 2014; 21: 519-531
        • Edwards P.A.
        • Kennedy M.A.
        • Mak P.A.
        LXRs; oxysterol-activated nuclear receptors that regulate genes controlling lipid homeostasis.
        Vasc. Pharmacol. 2002; 38: 249-256
        • Soumian S.
        • Gibbs R.
        • Davies A.
        • et al.
        mRNA expression of genes involved in lipid efflux and matrix degradation in occlusive and ectatic atherosclerotic disease.
        J. Clin. Pathol. 2005; 58: 1255-1260
        • Albrecht C.
        • Soumian S.
        • Amey J.S.
        • et al.
        ABCA1 expression in carotid atherosclerotic plaques.
        Stroke. 2004; 35: 2801-2806
        • Chinetti G.
        • Lestavel S.
        • Bocher V.
        • et al.
        PPARα and PPARγ activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway.
        Nat. Med. 2001; 7: 53-58
        • Mourmoura E.
        • Vasilaki A.
        • Giannoukas A.
        • et al.
        Evidence of deregulated cholesterol efflux in abdominal aortic aneurysm.
        Acta Histochem. 2016; 118: 97-108
        • Alonso J.
        • Galan M.
        • Marti-Pamies I.
        • et al.
        NOR-1/NR4A3 regulates the cellular inhibitor of apoptosis 2 (cIAP2) in vascular cells: role in the survival response to hypoxic stress.
        Sci. Rep. 2016; 6: 34056
        • Qing H.
        • Jones K.L.
        • Heywood E.B.
        • et al.
        Deletion of the NR4A nuclear receptor NOR1 in hematopoietic stem cells reduces inflammation but not abdominal aortic aneurysm formation.
        BMC Cardiovasc. Disord. 2017; 17: 271
        • Mullican S.E.
        • Zhang S.
        • Konopleva M.
        • et al.
        Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia.
        Nat. Med. 2007; 13: 730-735
        • Golledge J.
        • Norman P.E.
        Atherosclerosis and abdominal aortic aneurysm: cause, response, or common risk factors?.
        Arterioscler. Thromb. Vasc. Biol. 2010; 30: 1075-1077
        • Peshkova I.O.
        • Schaefer G.
        • Koltsova E.K.
        Atherosclerosis and aortic aneurysm - is inflammation a common denominator?.
        FEBS J. 2016; 283: 1636-1652