The PPARalpha/p16INK4a pathway inhibits vascular smooth muscle cell proliferation by repressing cell cycle-dependent telomerase activation.
Peroxisome proliferator-activated receptor (PPAR)alpha, the molecular target for fibrates used to treat dyslipidemia, exerts pleiotropic effects on vascular cells. In vascular smooth muscle cells (VSMCs), we have previously demonstrated that PPARalpha activation suppresses G(1)-->S cell cycle progression by targeting the cyclin-dependent kinase inhibitor p16(INK4a) (p16). In the present study, we demonstrate that this inhibition of VSMC proliferation by PPARalpha is mediated through a p16-dependent suppression of telomerase activity, which has been implicated in key cellular functions including proliferation. PPARalpha activation inhibited mitogen-induced telomerase activity by repressing the catalytic subunit telomerase reverse transcriptase (TERT) through negative cross-talk with an E2F-1-dependent trans-activation of the TERT promoter. This trans-repression involved the recruitment of the retinoblastoma (RB) family proteins p107 and p130 to the TERT promoter resulting in impaired E2F-1 binding, an effect that was dependent on p16. The inhibition of cell proliferation by PPARalpha activation was lost in VSMCs following TERT overexpression or knockdown, pointing to a key role of telomerase as a target for the antiproliferative effects of PPARalpha. Finally, we demonstrate that PPARalpha agonists suppress telomerase activation during the proliferative response following vascular injury, indicating that these findings are applicable in vivo. In concert, these results demonstrate that the antiproliferative effects of PPARalpha in VSMCs depend on the suppression of telomerase activity by targeting the p16/RB/E2F transcriptional cascade.
Gizard
Florence
F
Division of Endocrinology and Molecular Medicine, University of Kentucky College of Medicine, Lexington, KY 40536-0200, USA.
Nomiyama
Takashi
T
Zhao
Yue
Y
Findeisen
Hannes M
HM
Heywood
Elizabeth B
EB
Jones
Karrie L
KL
Staels
Bart
B
Bruemmer
Dennis
D
D000818:Animals; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D050171:Dyslipidemias / Q000201:enzymology / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D016193:G1 Phase / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008934:Mitogens / Q000378:metabolism / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology*; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D051381:Rats; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130 / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000502:physiology*; D019098:Telomerase / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D019941:Cyclin-Dependent Kinase Inhibitor p16; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; C493755:E2f1 protein, rat; D008934:Mitogens; D047493:PPAR alpha; C489485:Rbl1 protein, mouse; C493838:Rbl2 protein, mouse; C493839:Rbl2 protein, rat; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D019098:Telomerase; C509187:Tert protein, mouse