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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Figure 6

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p16 deficiency results in the induction of carotid artery hyperplasia th...
p16 deficiency results in the induction of carotid artery hyperplasia that is not inhibited by fenofibrate. Left carotid arteries from p16–/– C57BL/6J mice treated or not treated (n = 5/group) with fenofibrate were mechanically injured and analyzed after injury as described in Figure 5. (A) Topographic pattern of I/M area ratio. Values are mean ± SEM of the I/M ratios measured at the indicated distances from the junction on Masson’s trichrome–stained sections. *P ≤ 0.05, **P ≤ 0.01 vs. p16+/+ mice. No significant difference was found between fenofibrate-treated and untreated p16–/– mice. (B) Representative sections of mouse carotid arteries stained for morphometry or SMC. Carotid artery sections from untreated mice were stained with Masson’s trichrome or with an α-actin antibody at 50 and 25 μM from the junction, respectively. Scale bars: 300 μM. The internal elastic lamina is indicated by black arrows.