PPAR alpha inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a.
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.
Gizard
Florence
F
INSERM U545, Département d'Athérosclérose, Institut Pasteur de Lille et Faculté de Pharmacie, Université Lille II, Lille, France.
Amant
Carole
C
Barbier
Olivier
O
Bellosta
Stefano
S
Robillard
Romain
R
Percevault
Frédéric
F
Sevestre
Henry
H
Krimpenfort
Paul
P
Corsini
Alberto
A
Rochette
Jacques
J
Glineur
Corine
C
Fruchart
Jean-Charles
JC
Torpier
Gérard
G
Staels
Bart
B
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
D019941:Cyclin-Dependent Kinase Inhibitor p16; D006131:Growth Inhibitors; D047493:PPAR alpha; D016160:Retinoblastoma Protein; D051358:Cyclin-Dependent Kinase 4