title: PPARδ coordinates angiotensin II-induced senescence in vascular smooth muscle cells through PTEN-mediated inhibition of superoxide generation.
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.
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Korea.
authors.forename: Hyo Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Sun Ah
authors.initials: SA
authors.lastname: Ham
authors.forename: Min Young
authors.initials: MY
authors.lastname: Kim
authors.forename: Jung Seok
authors.initials: JS
authors.lastname: Hwang
authors.forename: Hanna
authors.initials: H
authors.lastname: Lee
authors.forename: Eun Sil
authors.initials: ES
authors.lastname: Kang
authors.forename: Taesik
authors.initials: T
authors.lastname: Yoo
authors.forename: Im Sun
authors.initials: IS
authors.lastname: Woo
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yabe-Nishimura
authors.forename: Kyung Shin
authors.initials: KS
authors.lastname: Paek
authors.forename: Jin-Hoi
authors.initials: JH
authors.lastname: Kim
authors.forename: Han Geuk
authors.initials: HG
authors.lastname: Seo
mesh_terms: D019943:Amino Acid Substitution; D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D020125:Mutation, Missense; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013481:Superoxides / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C091778:Ppard protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D013481:Superoxides; D000804:Angiotensin II; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse
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