Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
PPARα inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a
Florence Gizard, … , Gérard Torpier, Bart Staels
Florence Gizard, … , Gérard Torpier, Bart Staels
Published November 1, 2005
Citation Information: J Clin Invest. 2005;115(11):3228-3238. https://doi.org/10.1172/JCI22756.
View: Text | PDF
Research Article Cardiology

PPARα inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a

  • Text
  • PDF
Abstract

Vascular SMC proliferation is a crucial event in occlusive cardiovascular diseases. PPARα 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 PPARα controls SMC cell-cycle progression at the G1/S transition by targeting the cyclin-dependent kinase inhibitor and tumor suppressor p16INK4a (p16), resulting in an inhibition of retinoblastoma protein phosphorylation. PPARα 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, PPARα 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 PPARα inhibits SMC proliferation through p16. Thus, the PPARα/p16 pathway may be a potential pharmacological target for the prevention of cardiovascular occlusive complications of atherosclerosis.

Authors

Florence Gizard, Carole Amant, Olivier Barbier, Stefano Bellosta, Romain Robillard, Frédéric Percevault, Henry Sevestre, Paul Krimpenfort, Alberto Corsini, Jacques Rochette, Corine Glineur, Jean-Charles Fruchart, Gérard Torpier, Bart Staels

×

Figure 2

Options: View larger image (or click on image) Download as PowerPoint
PPARα activation increases p16 gene transcription. (A) Regulation of p16...
PPARα activation increases p16 gene transcription. (A) Regulation of p16 mRNA levels in hSMCs and mSMCs. Quantitative RT-PCR analyses were performed on RNA from Ad-GFP or Ad-PPARα–infected hSMCs treated or not treated with GW7647 (600 nM, upper panel) and on PPARα–/– and PPARα+/+ Sv/129 mSMCs treated or not treated with Wy14,643 (6 μM, lower panel). Values are expressed relative to the controls (mRNA levels in PPARα+/+ mSMCs or hSMCs at T0) set as 1. (B) Induction of human p16 promoter activity by ligand-activated PPARα. pGL2 luciferase reporter constructs driven by the indicated p16 promoter deletion fragments (0.1 μg) were cotransfected in HeLa cells with or without pSG5 PPARα expression plasmid (0.3 μg). Cells were subsequently treated with fenofibric acid (100 μM) for 10 hours. Results (mean ± SD) from 1 representative experiment (n = 3) out of 3 is shown. (C) In vitro binding of PPARα to the p16DR1. EMSAs were carried out with end-labeled consensus DR1 (DR1cons), wild-type p16DR1 (p16DR1wt), or mutated p16DR1 (p16DR1mt) probes in the presence of unprogrammed reticulocyte lysate, RXR, PPARα, or both RXR and PPARα as indicated. (D) In-cell occupation of the p16 gene promoter by PPARα. Soluble chromatin was prepared from hSMCs treated with or without fenofibric acid (250 μM). IP was performed with anti-Sp1 or anti-PPARα antibodies, and DNA was amplified using specific primer pairs. Bottom lane shows schematic diagram depicting the fragments of the p16 and β-actin genes that were amplified. The nucleotide positions are indicated relative to the ATG. In panels B and D, A, B, and C denote the 3 Sp1-binding sites identified by Myohanen et al. (26) (see Results), and the putative transcription start site of the p16 promoter is indicated by an arrow.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts