title: PPAR alpha 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. PPARalpha 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 PPARalpha controls SMC cell-cycle progression at the G1/S transition by targeting the cyclin-dependent kinase inhibitor and tumor suppressor p16(INK4a) (p16), resulting in an inhibition of retinoblastoma protein phosphorylation. PPARalpha 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, PPARalpha 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 PPARalpha inhibits SMC proliferation through p16. Thus, the PPARalpha/p16 pathway may be a potential pharmacological target for the prevention of cardiovascular occlusive complications of atherosclerosis.
authors.affiliation: INSERM U545, Département d'Athérosclérose, Institut Pasteur de Lille et Faculté de Pharmacie, Université Lille II, Lille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Gizard
authors.forename: Carole
authors.initials: C
authors.lastname: Amant
authors.forename: Olivier
authors.initials: O
authors.lastname: Barbier
authors.forename: Stefano
authors.initials: S
authors.lastname: Bellosta
authors.forename: Romain
authors.initials: R
authors.lastname: Robillard
authors.forename: Frédéric
authors.initials: F
authors.lastname: Percevault
authors.forename: Henry
authors.initials: H
authors.lastname: Sevestre
authors.forename: Paul
authors.initials: P
authors.lastname: Krimpenfort
authors.forename: Alberto
authors.initials: A
authors.lastname: Corsini
authors.forename: Jacques
authors.initials: J
authors.lastname: Rochette
authors.forename: Corine
authors.initials: C
authors.lastname: Glineur
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Fruchart
authors.forename: Gérard
authors.initials: G
authors.lastname: Torpier
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
mesh_terms: D000818:Animals; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D051358:Cyclin-Dependent Kinase 4 / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics; D016193:G1 Phase / Q000235:genetics; D006131:Growth Inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D006965:Hyperplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D047493:PPAR alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology; D017539:Tunica Intima / Q000166:cytology / Q000473:pathology*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D006131:Growth Inhibitors; D047493:PPAR alpha; D016160:Retinoblastoma Protein; D051358:Cyclin-Dependent Kinase 4