PPARδ Coordinates Angiotensin II-induced Senescence in Vascular Smooth Muscle Cells through PTEN-mediated Inhibition of Superoxide Generation*

  1. Han Geuk Seo‡,3
  1. From the ‡Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Korea,
  2. the §Department of Pharmacology, Gyeongsang National University School of Medicine, Jinju 660-751, Korea,
  3. the Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan, and
  4. the ‖Department of Nursing, Semyung University, Jechon 390-711, Korea
  1. ↵2 To whom correspondence may be addressed: Hwayang-Dong, Gwangjin-Gu, Seoul, Korea. Tel.: 82-2-450-3687; Fax: 82-2-458-5414; E-mail: jhkim541{at}konkuk.ac.kr.
  2. ↵3 To whom correspondence may be addressed: 1 Hwayang-Dong, Gwangjin-Gu, Seoul 143-701, Korea. Tel.: 82-2-450-0428; Fax: 82-2-455-1044; E-mail: hgseo{at}konkuk.ac.kr.

  1. ↵1 Both authors contributed equally to this work.

Background: PPARδ is a ligand-activated transcriptional factor that has been implicated in the vascular homeostasis.

Results: Activation of PPARδ significantly attenuated Ang II-induced senescence of VSMCs by up-regulation of PTEN and ensuing modulation of the PI3K/Akt signaling.

Conclusion: PPARδ inhibits Ang II-induced senescence of VSMCs via PTEN-mediated inhibition of ROS generation.

Significance: PPARδ provides a novel insight into the treatment of atherosclerotic vascular disease.

Abstract

Cellular senescence-associated changes in blood vessels have been implicated in aging and age-related cardiovascular disorders. Here, we demonstrate that peroxisome proliferator-activated receptor (PPAR) δ coordinates angiotensin (Ang) II-induced senescence of human vascular smooth muscle cells (VSMCs). Activation of PPARδ by GW501516, a specific ligand for PPARδ, significantly attenuated Ang II-induced generation of superoxides and suppressed senescence of VSMCs. A marked increase in the levels of p53 and p21 induced by Ang II was blunted by the treatment with GW501516. Ligand-activated PPARδ up-regulated expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and suppressed the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Knockdown of PTEN with siRNA abrogated the effects of PPARδ on cellular senescence, on PI3K/Akt signaling, and on generation of ROS in VSMCs treated with Ang II. Finally, administration of GW501516 to apoE-deficient mice treated with Ang II significantly reduced the number of senescent cells in the aorta, where up-regulation of PTEN with reduced levels of phosphorylated Akt and ROS was demonstrated. Thus, ligand-activated PPARδ confers resistance to Ang II-induced senescence by up-regulation of PTEN and ensuing modulation of the PI3K/Akt signaling to reduce ROS generation in vascular cells.

Footnotes

  • ↵* This work was supported in part by the Mid-career Research Program and MRC Program through an NRF grant funded by MEST (2011-0012427 and 2011-0006200) and Next-Generation BioGreen 21 Program (PJ007980), Rural Development Administration, Republic of Korea.

  • ↵Graphic The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S7.

  • Received January 18, 2011.
  • Revision received October 27, 2011.
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  1. First Published on November 9, 2011 doi: 10.1074/jbc.M111.222562 The Journal of Biological Chemistry 286, 44585-44593.
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