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

Florence Gizard, Carole Amant, Olivier Barbier, Stefano Bellosta, Romain Robillard, Frédéric Percevault, Henry Sevestre, Paul Krimpenfort, Alberto Corsini, Jacques Rochette, Corine Glineur, Jean Charles Fruchart, Gérard Torpier, Bart Staels

Research output: Contribution to journalArticle

Abstract

Vascular SMC proliferation is a crucial event in occlusive cardiovascular diseases. PPARα 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 PPARα controls SMC cell-cycle progression at the G1/S transition by targeting the cyclin-dependent kinase inhibitor and tumor suppressor p16INK4a (p16), resulting in an inhibition of retinoblastoma protein phosphorylation. PPARα 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, PPARα activation inhibits SMC growth in vivo, and this effect requires p16 expression. These results identify an unexpected role for p16 in SMC cell-cycle control and demonstrate that PPARα inhibits SMC proliferation through p16. Thus, the PPARα/p16 pathway may be a potential pharmacological target for the prevention of cardiovascular occlusive complications of atherosclerosis.

Original languageEnglish
Pages (from-to)3228-3238
Number of pages11
JournalJournal of Clinical Investigation
Volume115
Issue number11
DOIs
Publication statusPublished - Nov 2005

ASJC Scopus subject areas

  • Medicine(all)

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    Gizard, F., Amant, C., Barbier, O., Bellosta, S., Robillard, R., Percevault, F., Sevestre, H., Krimpenfort, P., Corsini, A., Rochette, J., Glineur, C., Fruchart, J. C., Torpier, G., & Staels, B. (2005). PPARα inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a. Journal of Clinical Investigation, 115(11), 3228-3238. https://doi.org/10.1172/JCI22756