A central role of interferon regulatory factor-1 for the limitation of neointimal hyperplasia.
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.
Wessely
Rainer
R
Deutsches Herzzentrum and 1 Medizinische Klinik, Klinikum rechts der Isar, Technische Universität, Munich, Germany. rwessely@dhm.mhn.de
Hengst
Ludger
L
Jaschke
Birgit
B
Wegener
Franziska
F
Richter
Thomas
T
Lupetti
Raffaella
R
Paschalidis
Makarios
M
Schömig
Albert
A
Brandl
Richard
R
Neumann
Franz-Josef
FJ
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*
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D014157:Transcription Factors