PPARα inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a
Florence Gizard, … , Gérard Torpier, Bart Staels
Florence Gizard, … , Gérard Torpier, Bart Staels
Published November 1, 2005
Citation Information: J Clin Invest. 2005;115(11):3228-3238. https://doi.org/10.1172/JCI22756.
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Research Article Cardiology

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

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.

Authors

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

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PPARα activation increases p16 protein levels and p16-CDK4 interaction a...
PPARα activation increases p16 protein levels and p16-CDK4 interaction and decreases CDK4-mediated pRB phosphorylation in hSMCs and mSMCs. (A–C) Protein extracts of hSMCs infected and treated for 12 hours (A) or 24 hours (B and C) with GW7647 (600 nM) were submitted to Western blot analysis either directly (A and B) or after IP with an anti-CDK4 antibody (C). Cellular p16 protein levels (A) and in-cell CDK4-mediated pRB phosphorylation (B) were measured using an antibody specific for p16 or an anti-pRB antibody recognizing a site specifically phosphorylated by cyclin D1/CDK4 (P∼Ser780-ppRB) (28), respectively. (C) Anti-CDK4 immunoprecipitates were assayed for kinase activity using the 769–921 pRB fragment as substrate (63) (top panel), or analyzed by Western blot using specific anti-p16 (middle panel) or anti-CDK4 antibodies (lower panel). (D) Protein extracts of PPARα–/– or PPARα+/+ C57BL/6J mSMCs treated for 24 hours with Wy14,643 (6 μM) were submitted to Western blot analysis using the anti-p16 and anti–P∼Ser780-ppRB antibodies.