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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

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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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Figure 1

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PPARα inhibits SMC G1/S progression. (A and B) G1-arrested hSMCs (A) and...
PPARα inhibits SMC G1/S progression. (A and B) G1-arrested hSMCs (A) and PPARα–/– or PPARα+/+ Sv/129 mSMCs (B) resumed growth at T0 in normal GM. The indicated concentrations of GW7647, Wy14,643 (10 μM), or vehicle (Me2SO) were added in the normal GM. Cells were harvested at the indicated times for measure of DNA content (expressed as arbitrary units). Values are the mean ± SEM of triplicate points from a single experiment (n = 3/time point), which was repeated with 3 different cell preparations of primary SMCs with similar results. *P ≤ 0.05; ***P ≤ 0.001 vs. vehicle-treated hSMCs (A). Values in B followed by different symbols are statistically significantly different from each other. (C) Western blot analysis of in-cell pRB phosphorylation was performed using an anti-pRB antibody recognizing all species of the Rb gene product on protein extracts (30 μg) from Ad-GFP or Ad-PPARα–infected hSMCs and treated with vehicle or GW7647 (600 nM) for 10 hours.

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