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(Circulation Research. 2008;103:1155.)
© 2008 American Heart Association, Inc.

Molecular Medicine

The PPAR/p16^INK4a Pathway Inhibits Vascular Smooth Muscle Cell Proliferation by Repressing Cell Cycle–Dependent Telomerase Activation

Florence Gizard, Takashi Nomiyama, Yue Zhao, Hannes M. Findeisen, Elizabeth B. Heywood, Karrie L. Jones, Bart Staels, Dennis Bruemmer

From the Division of Endocrinology and Molecular Medicine (F.G., T.N., Y.Z., H.M.F., E.B.H., K.L.J., D.B.), University of Kentucky College of Medicine, Lexington; Institut Pasteur de Lille (B.S.), Département d’Athérosclérose, Lille, France; Institut National de la Santé et de la Recherche Médicale (B.S.), U545, Lille, France; and Université de Lille 2 (B.S.), Lille, France.

Correspondence to Dennis Bruemmer, MD, University of Kentucky College of Medicine, Division of Endocrinology and Molecular Medicine, Wethington Health Sciences Building, Room 575, 900 S Limestone St, Lexington, KY 40536-0200. E-mail Dennis.Bruemmer{at}uky.edu

Peroxisome proliferator-activated receptor (PPAR), 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 PPAR activation suppresses G₁S 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 PPAR is mediated through a p16-dependent suppression of telomerase activity, which has been implicated in key cellular functions including proliferation. PPAR 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 PPAR 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 PPAR. Finally, we demonstrate that PPAR 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 PPAR in VSMCs depend on the suppression of telomerase activity by targeting the p16/RB/E2F transcriptional cascade.

Key Words: PPAR • telomerase • smooth muscle cells • transcriptional regulation • p16^INK4a

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