title: Nuclear receptor Nurr1 is expressed in and is associated with human restenosis and inhibits vascular lesion formation in mice involving inhibition of smooth muscle cell proliferation and inflammation.
abstract: BACKGROUND
  Restenosis is the major drawback of percutaneous coronary interventions involving excessive activation and proliferation of vascular smooth muscle cells (SMCs). The nuclear receptor Nurr1 is an early response gene known mainly for its critical role in the development of dopamine neurons. In the present study, we investigated Nurr1 in human and experimental vascular restenosis.
  
  
  RESULTS
  In a prospective cohort of 601 patients undergoing percutaneous coronary intervention, including stent placement, we found a strong association between Nurr1 haplotypes and in-stent restenosis risk. Furthermore, Nurr1 is specifically expressed in human in-stent restenosis and induced in cultured human SMCs in response to serum or tumor necrosis factor-alpha. Lentivirus-mediated gain- and loss-of-function experiments in SMCs demonstrated that overexpression of Nurr1 inhibited proliferation, consistent with increased expression of the key cell-cycle inhibitor p27(Kip1), whereas Nurr1 silencing enhanced SMC growth. The tumor necrosis factor-alpha-induced proinflammatory response of SMCs is inhibited by Nurr1, as reflected by reduced interleukin-1beta, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 expression. Consistent with our in vitro data, endogenous Nurr1 reduced wire injury-induced proliferation and vascular lesion formation in carotid arteries of ApoE(-/-) mice.
  
  
  CONCLUSIONS
  Nurr1 haplotypes are associated with human restenosis risk, and Nurr1 is expressed in human in-stent restenosis. In SMCs, Nurr1 inhibits proliferation and inflammatory responses, which explains the inhibition of SMC-rich lesion formation in mice. The recently identified small-molecule drugs that enhance the activity of Nurr1 reveal this nuclear receptor as an attractive novel target for (local) intervention in restenosis.
authors.affiliation: Departments of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Peter I
authors.initials: PI
authors.lastname: Bonta
authors.forename: Thijs W H
authors.initials: TW
authors.lastname: Pols
authors.forename: Claudia M
authors.initials: CM
authors.lastname: van Tiel
authors.forename: Mariska
authors.initials: M
authors.lastname: Vos
authors.forename: E Karin
authors.initials: EK
authors.lastname: Arkenbout
authors.forename: Jakub
authors.initials: J
authors.lastname: Rohlena
authors.forename: Karel T
authors.initials: KT
authors.lastname: Koch
authors.forename: Moniek P M
authors.initials: MP
authors.lastname: de Maat
authors.forename: Michael W T
authors.initials: MW
authors.lastname: Tanck
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: de Winter
authors.forename: Hans
authors.initials: H
authors.lastname: Pannekoek
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.forename: Carlie J M
authors.initials: CJ
authors.lastname: de Vries
mesh_terms: D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000235:genetics* / Q000628:therapy; D023903:Coronary Restenosis / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D003331:Coronary Vessels / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D051379:Mice; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000473:pathology* / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000502:physiology; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D015607:Stents; D014657:Vasculitis / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; C539882:NR4A2 protein, human; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2