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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:257.)
© 2004 American Heart Association, Inc.

Vascular Biology

Interferon Regulatory Factor-1 Mediates PPAR-Induced Apoptosis in Vascular Smooth Muscle Cells

Yiming Lin; Xiaojun Zhu; Farron L. Mclntee; Hailian Xiao; Jifeng Zhang; Mingui Fu; Yuqing E. Chen

From the Cardiovascular Research Institute (Y.L., F.L.M., H.X., J.Z., M.F., Y.E.C.), Morehouse School of Medicine, Atlanta, GA and the Cardiovascular Research Institute (X.Z., Y.E.C.), Peking University Health Science Center, Beijing 100083, China.

Correspondence to Yuqing E. Chen, Cardiovascular Research Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA 30310. E-mail echen{at}msm.edu

Objective— Peroxisome proliferator-activated receptor (PPAR) possesses general beneficial effects on the cardiovascular system, such as inhibition of vascular lesion formation and atherosclerosis. However, molecular mechanisms for these effects are yet to be fully defined. The aim of this study is to elucidate whether interferon regulatory factor-1 (IRF-1), a transcriptional factor with anti-proliferative and pro-apoptotic properties, mediates PPAR-induced apoptosis in vascular smooth muscle cells (VSMCs).

Methods and Results— Using Northern and Western blot analyses, we documented that PPAR ligands, including ciglitazone, troglitazone, and GW7845, significantly increased IRF-1 expression in VSMCs; however, the PPAR ligand (Wy14643) and PPAR ligand (GW0742) did not affect its expression. PPAR-induced IRF-1 expression was abrogated by pretreatment with the PPAR antagonist GW9662. In contrast, adenoviral expression of PPAR in VSMCs dramatically increased IRF-1 level. Furthermore, PPAR activation increased IRF-1 promoter activity but did not affect IRF-1 mRNA stability. Finally, reducing IRF-1 expression by antisense technology attenuated PPAR-induced VSMC apoptosis through decreasing cyclin-dependent kinase inhibitor p21^cip1 and caspase-3 activity.

Conclusion— Our data demonstrate that IRF-1 is a novel PPAR target gene and mediates PPAR-induced VSMC apoptosis.

Key Words: peroxisome proliferator-activated receptor • interferon regulatory factor-1 • vascular smooth muscle cells • gene expression • apoptosis • atherosclerosis

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