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The PPARalpha/p16INK4a pathway inhibits vascular smooth muscle cell proliferation by repressing cell cycle-dependent

Florence Gizard1, Takashi Nomiyama, Yue Zhao

  • 1Division of Endocrinology and Molecular Medicine, University of Kentucky College of Medicine, Lexington, KY 40536-0200, USA.

Circulation Research
|September 27, 2008
PubMed

Insights

Peroxisome proliferator-activated receptor (PPAR)alpha activation inhibits vascular smooth muscle cell proliferation by suppressing telomerase activity. This effect is mediated by the p16/retinoblastoma protein/E2F-1 pathway, impacting vascular injury responses.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cell Biology
  • Pharmacology

Background:

  • Peroxisome proliferator-activated receptor (PPAR)alpha is a target for dyslipidemia treatment, with known vascular cell effects.
  • PPARalpha activation suppresses G(1)-->S cell cycle progression in vascular smooth muscle cells (VSMCs) via p16(INK4a) (p16).

Purpose of the Study:

  • To investigate the role of telomerase activity in PPARalpha-mediated suppression of VSMC proliferation.
  • To elucidate the molecular mechanisms linking PPARalpha, p16, and telomerase in VSMCs.

Main Methods:

  • Assessed telomerase activity and expression of its catalytic subunit, telomerase reverse transcriptase (TERT), in VSMCs.
  • Utilized overexpression and knockdown techniques for TERT and p16.
  • Investigated the interaction of retinoblastoma (RB) family proteins (p107, p130) and E2F-1 at the TERT promoter.
  • Examined PPARalpha agonist effects on telomerase activation in a vascular injury model in vivo.

Main Results:

  • PPARalpha activation inhibited mitogen-induced telomerase activity by repressing TERT promoter trans-activation.
  • This repression involved p16-dependent recruitment of p107/p130 to the TERT promoter, impairing E2F-1 binding.
  • Loss of antiproliferative effect upon TERT overexpression or knockdown confirmed telomerase as a key target.
  • PPARalpha agonists suppressed telomerase activation in response to vascular injury.

Conclusions:

  • PPARalpha's antiproliferative effects in VSMCs are dependent on telomerase suppression.
  • The mechanism involves the p16/RB/E2F-1 transcriptional cascade targeting TERT.
  • These findings highlight a novel pathway for PPARalpha in regulating vascular cell proliferation and response to injury.

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