TY - JOUR
T1 - A central role of interferon regulatory factor-1 for the limitation of neointimal hyperplasia
AU - Wessely, Rainer
AU - Hengst, Ludger
AU - Jaschke, Birgit
AU - Wegener, Franziska
AU - Richter, Thomas
AU - Lupetti, Raffaella
AU - Paschalidis, Makarios
AU - Schömig, Albert
AU - Brandl, Richard
AU - Neumann, Franz Josef
N1 - Funding Information:
This study was supported by a grant awarded to R.W. (We 1811/3-1 and 3-2) from the Deutsche Forschungsgemeinschaft (DFG). R.B. was also supported by a DFG grant (Br 1583/1-2). We are indebted to Angelika Dötterl, Renate Hegenloh and Erika Schneider for expert technical assistance. We gratefully acknowledge the expertise of Michael Weber in genotyping IRF-1-deficient mice. We thank J.L. Stein and P. Vaughan for IRF-1 cDNA, T. Mak for IRF-1 knockout mice and B. Vogelstein for the p21 promoter construct and p53 expression plasmids.
PY - 2003/1/15
Y1 - 2003/1/15
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/0037439418
U2 - 10.1093/hmg/ddg018
DO - 10.1093/hmg/ddg018
M3 - Review article
C2 - 12499398
AN - SCOPUS:0037439418
SN - 0964-6906
VL - 12
SP - 177
EP - 187
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 2
ER -