Journal Article

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

Rainer Wessely, Ludger Hengst, Birgit Jaschke, Franziska Wegener, Thomas Richter, Raffaella Lupetti, Makarios Paschalidis, Albert Schömig, Richard Brandl and Franz-Josef Neumann

in Human Molecular Genetics

Volume 12, issue 2, pages 177-187
Published in print January 2003 | ISSN: 0964-6906
Published online January 2003 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddg018
A central role of interferon regulatory factor-1 for the limitation of neointimal hyperplasia

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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.

Journal Article.  6221 words.  Illustrated.

Subjects: Genetics and Genomics

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