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

126 Citations (Scopus)

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

Fingerprint

Tunica Intima
Peroxisome Proliferator-Activated Receptors
Vascular Smooth Muscle
Smooth Muscle Myocytes
Hyperplasia
Cell Proliferation
Neoplasms
Cell Cycle Checkpoints
Sp1 Transcription Factor
p16 Genes
Retinoblastoma Protein
Cyclin-Dependent Kinases
Response Elements
Cytoplasmic and Nuclear Receptors
Growth
Lipid Metabolism
Blood Vessels
Atherosclerosis
Cardiovascular Diseases
Binding Sites

ASJC Scopus subject areas

  • Medicine(all)

Cite this

PPARα inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a. / Gizard, Florence; Amant, Carole; Barbier, Olivier; Bellosta, Stefano; Robillard, Romain; Percevault, Frédéric; Sevestre, Henry; Krimpenfort, Paul; Corsini, Alberto; Rochette, Jacques; Glineur, Corine; Fruchart, Jean Charles; Torpier, Gérard; Staels, Bart.

In: Journal of Clinical Investigation, Vol. 115, No. 11, 11.2005, p. 3228-3238.

Research output: Contribution to journalArticle

Gizard, F, Amant, C, Barbier, O, Bellosta, S, Robillard, R, Percevault, F, Sevestre, H, Krimpenfort, P, Corsini, A, Rochette, J, Glineur, C, Fruchart, JC, 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, vol. 115, no. 11, pp. 3228-3238. https://doi.org/10.1172/JCI22756
Gizard, Florence ; Amant, Carole ; Barbier, Olivier ; Bellosta, Stefano ; Robillard, Romain ; Percevault, Frédéric ; Sevestre, Henry ; Krimpenfort, Paul ; Corsini, Alberto ; Rochette, Jacques ; Glineur, Corine ; Fruchart, Jean Charles ; Torpier, Gérard ; Staels, Bart. / PPARα inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a. In: Journal of Clinical Investigation. 2005 ; Vol. 115, No. 11. pp. 3228-3238.
@article{ac63f5334bec49ef82d13859d29514ae,
title = "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.",
author = "Florence Gizard and Carole Amant and Olivier Barbier and Stefano Bellosta and Romain Robillard and Fr{\'e}d{\'e}ric Percevault and Henry Sevestre and Paul Krimpenfort and Alberto Corsini and Jacques Rochette and Corine Glineur and Fruchart, {Jean Charles} and G{\'e}rard Torpier and Bart Staels",
year = "2005",
month = "11",
doi = "10.1172/JCI22756",
language = "English",
volume = "115",
pages = "3228--3238",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "11",

}

TY - JOUR

T1 - PPARα inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a

AU - Gizard, Florence

AU - Amant, Carole

AU - Barbier, Olivier

AU - Bellosta, Stefano

AU - Robillard, Romain

AU - Percevault, Frédéric

AU - Sevestre, Henry

AU - Krimpenfort, Paul

AU - Corsini, Alberto

AU - Rochette, Jacques

AU - Glineur, Corine

AU - Fruchart, Jean Charles

AU - Torpier, Gérard

AU - Staels, Bart

PY - 2005/11

Y1 - 2005/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=27644590901&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=27644590901&partnerID=8YFLogxK

U2 - 10.1172/JCI22756

DO - 10.1172/JCI22756

M3 - Article

C2 - 16239970

AN - SCOPUS:27644590901

VL - 115

SP - 3228

EP - 3238

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 11

ER -