PPARα inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a

Vascular SMC proliferation is a crucial event in occlusive cardiovascular diseases. PPAR alpha is a nuclear receptor controlling lipid metabolism and inflammation, but its role in the regulation of SMC growth remains to be established. Here, we show that PPARa. controls SMC cell-cycle progression at the G(1)/S transition by targeting the cyclin-dependent kinase inhibitor and tumor suppressor p16(INK4a) (p16), resulting in an inhibition of retinoblastoma protein phosphorylation. PPARa activates p16 gene transcription by both binding to a canonical PPAR-response element and interacting with the transcription factor Sp1 at specific proximal Sp1-binding sites of the p16 promoter. In a carotid arterial-injury mouse model, p16 deficiency results in an enhanced SMC proliferation underlying intimal hyperplasia.. Moreover, PPAR alpha activation inhibits SMC growth in vivo, and this effect requires p 16 expression. These results identify an unexpected role for p16 in SMC cell-cycle control and demonstrate that PPARa. inhibits SMC proliferation through p16. Thus, the PPAR alpha/p16 pathway may be a potential pharmacological target for the prevention of cardiovascular occlusive complications of atherosclerosis.