Document Detail

PPARδ coordinates angiotensin II-induced senescence in vascular smooth muscle cells through PTEN-mediated inhibition of superoxide generation.
MedLine Citation:
PMID:  22072715     Owner:  NLM     Status:  MEDLINE    
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.
Hyo Jung Kim; Sun Ah Ham; Min Young Kim; Jung Seok Hwang; Hanna Lee; Eun Sil Kang; Taesik Yoo; Im Sun Woo; Chihiro Yabe-Nishimura; Kyung Shin Paek; Jin-Hoi Kim; Han Geuk Seo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-11-09
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-26     Completed Date:  2012-02-27     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  44585-93     Citation Subset:  IM    
Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Korea.
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MeSH Terms
Amino Acid Substitution
Angiotensin II / genetics,  metabolism*
Aorta / cytology,  metabolism
Cell Aging / physiology*
Cells, Cultured
Gene Knockdown Techniques
Mice, Mutant Strains
Muscle, Smooth, Vascular / cytology,  metabolism*
Mutation, Missense
Myocytes, Smooth Muscle / cytology,  metabolism*
PTEN Phosphohydrolase / genetics,  metabolism*
Phosphatidylinositol 3-Kinases / genetics,  metabolism
Proto-Oncogene Proteins c-akt / physiology
Receptors, Cytoplasmic and Nuclear / genetics,  metabolism*
Signal Transduction / physiology
Superoxides / metabolism*
Tumor Suppressor Protein p53 / genetics,  metabolism
Reg. No./Substance:
0/Ppard protein, mouse; 0/Receptors, Cytoplasmic and Nuclear; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 11062-77-4/Superoxides; 11128-99-7/Angiotensin II; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC Proteins c-akt; EC protein, human; EC protein, mouse; EC Phosphohydrolase

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