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 inhibits neointima formation after mechanical carotid i...
PPARα activation inhibits neointima formation after mechanical carotid injury. Left carotid arteries were performed on PPARα–/– (n = 6) or PPARα+/+ Sv/129 mice treated (n = 5) or not (n = 8) with fenofibrate. (A) Topographic pattern of I/M area ratio 3 weeks after injury. Values are mean ± SEM of the I/M ratios measured on Masson’s trichrome–stained sections at the indicated distances from the junction between the external and internal branches of the left carotid artery (reference section at 0 μM). *P ≤ 0.05 vs. wild-type sections. (B) Representative carotid sections of uninjured right and injured left carotids at 50 μm from the junction stained with Masson’s trichrome. Scale bars: 100 μM. The internal elastic lamina delineating the neointima is indicated by a black arrow. (C) Representative sections of mouse carotid arteries immunostained for SMC (α-actin staining, brown, upper panel) or for proliferation marking (PCNA immunostaining to identify cells in S phase, brown, lower panel) at 150 μm and 100 μm from the junction, respectively. No intima was found in uninjured right carotids. Scale bars: 100 μM. The I/M ratio is equal to 0 in uninjured right carotid because intima of the healthy carotid artery is only composed of the monolayer endothelial cells. (D) Fenofibrate induces p16 mRNA levels in injured carotid arteries. Mouse carotid arteries were dissected at the indicated times after intraluminal mechanical injury of the left artery. p16 mRNA levels in the carotid segments are expressed as means ± SEM (n = 5) of fold change relative to the uninjured wild-type arteries, arbitrarily set to 1. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 vs. uninjured wild-type mice.