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

OBJECTIVE: Peroxisome proliferator-activated receptor gamma (PPARgamma) 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 PPARgamma-induced apoptosis in vascular smooth muscle cells (VSMCs). METHODS AND RESULTS: Using Northern and Western blot analyses, we documented that PPARgamma ligands, including ciglitazone, troglitazone, and GW7845, significantly increased IRF-1 expression in VSMCs; however, the PPARalpha ligand (Wy14643) and PPARdelta ligand (GW0742) did not affect its expression. PPARgamma-induced IRF-1 expression was abrogated by pretreatment with the PPARgamma antagonist GW9662. In contrast, adenoviral expression of PPARgamma in VSMCs dramatically increased IRF-1 level. Furthermore, PPARgamma activation increased IRF-1 promoter activity but did not affect IRF-1 mRNA stability. Finally, reducing IRF-1 expression by antisense technology attenuated PPARgamma-induced VSMC apoptosis through decreasing cyclin-dependent kinase inhibitor p21(cip1) and caspase-3 activity. CONCLUSIONS: Our data demonstrate that IRF-1 is a novel PPARgamma target gene and mediates PPARgamma-induced VSMC apoptosis.