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Human Molecular Genetics, 2003, Vol. 12, No. 2 177-187
© 2003 Oxford University Press

A central role of interferon regulatory factor-1 for the limitation of neointimal hyperplasia

Rainer Wessely1,*, Ludger Hengst2, Birgit Jaschke1, Franziska Wegener1, Thomas Richter3, Raffaella Lupetti2, Makarios Paschalidis1, Albert Schömig1, Richard Brandl4 and Franz-Josef Neumann1

1Deutsches Herzzentrum and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität, Munich, Germany, 2Max Planck Institut für Biochemie, Martinsried, Germany, 3Institut für Allgemeine Pathologie und Pathologische Anatomie, Klinikum rechts der Isar, Technische Universität, Munich, Germany and 4Abteilung für Gefässchirurgie, Klinikum rechts der Isar, Technische Universität, Munich, Germany

Received September 30, 2002; Accepted November 15, 2002

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 G1 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.

* To whom correspondence should be addressed at: Deutsches Herzzentrum, Lazarettstrasse 36, 80636 München, Germany. Tel: +49 8912181514; Fax: +49 8912184013; Email: rwessely{at}dhm.mhn.de


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