title: A central role of interferon regulatory factor-1 for the limitation of neointimal hyperplasia.
abstract: Neointima formation, the leading cause of restenosis after catheter angioplasty, is a paradigm for vascular proliferative responses. Neointima formation is self-limiting after a variable degree of tissue growth, causing significant renarrowing in a substantial number of patients. To investigate the mechanisms that limit neointima formation we studied the role of the transcription factor IRF-1, which is a regulator of interferons and a tumor suppressor. We demonstrate that IRF-1 is highly regulated in human vascular lesions and exhibits a growth inhibitory function in coronary artery smooth muscle cells (CASMC). IRF-1 deficient mice display a high grade of susceptibility towards neointima formation following vessel injury. IRF-1 leads to G(1) cell cycle arrest in CASMC and induces the CDK inhibitor p21. In addition, IRF-1 induces NO production, which is known to attenuate endothelial dysfunction. Mitogen-mediated cellular migration is abrogated by IRF-1. In conclusion, IRF-1 displays pleiotropic anti-restenotic activities in vascular restenosis through transcriptional activation of several relevant mechanisms that limit neointima formation. These findings suggest an important role of this transcription factor as an endogenous inhibitor of neointimal growth following vessel injury and it is likely that IRF-1 regulation also plays a role in the pathophysiology of primary atherosclerosis. In addition, IRF-1 may be an interesting target for interventions to prevent neointimal hyperplasia.
authors.affiliation: Deutsches Herzzentrum and 1 Medizinische Klinik, Klinikum rechts der Isar, Technische Universität, Munich, Germany. rwessely@dhm.mhn.de
authors.forename: Rainer
authors.initials: R
authors.lastname: Wessely
authors.forename: Ludger
authors.initials: L
authors.lastname: Hengst
authors.forename: Birgit
authors.initials: B
authors.lastname: Jaschke
authors.forename: Franziska
authors.initials: F
authors.lastname: Wegener
authors.forename: Thomas
authors.initials: T
authors.lastname: Richter
authors.forename: Raffaella
authors.initials: R
authors.lastname: Lupetti
authors.forename: Makarios
authors.initials: M
authors.lastname: Paschalidis
authors.forename: Albert
authors.initials: A
authors.lastname: Schömig
authors.forename: Richard
authors.initials: R
authors.lastname: Brandl
authors.forename: Franz-Josef
authors.initials: FJ
authors.lastname: Neumann
mesh_terms: D000800:Angioplasty, Balloon; D000818:Animals; D001161:Arteriosclerosis / Q000503:physiopathology*; D018929:Cell Culture Techniques; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D006965:Hyperplasia / Q000276:immunology / Q000473:pathology*; D050856:Interferon Regulatory Factor-1; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D017539:Tunica Intima / Q000473:pathology*
chemical_list: D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D014157:Transcription Factors