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

Abstract

Objective-Peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ-induced apoptosis in vascular smooth muscle cells (VSMCs). Methods and Results-Using Northern and Western blot analyses, we documented that PPARγ ligands, including ciglitazone, troglitazone, and GW7845, significantly increased IRF-1 expression in VSMCs; however, the PPARα ligand (Wyl4643) and PPARδ ligand (GW0742) did not affect its expression. PPARγ-induced IRF-1 expression was abrogated by pretreatment with the PPARγ antagonist GW9662. In contrast, adenoviral expression of PPARγ in VSMCs dramatically increased IRF-1 level. Furthermore, PPARγ activation increased IRF-1 promoter activity but did not affect IRF-1 mRNA stability. Finally, reducing IRF-1 expression by antisense technology attenuated PPARγ-induced VSMC apoptosis through decreasing cyclin-dependent kinase inhibitor p21cip1 and caspase-3 activity. Conclusion-Our data demonstrate that IRF-1 is a novel PPARγ target gene and mediates PPARγ-induced VSMC apoptosis.