Peroxisome proliferator-activated receptor γ coactivator-1α is a central negative regulator of vascular senescence

• Type of Material: Article
• Authors: ShiQin Xiong, Emory University; Gloria Salazar, Emory University; Nikolay Patrushev, Emory University; Minhui Ma, Emory University; Farshad Forouzandeh, Emory University; Lu Hilenski, Emory University; R Wayne Alexander, Emory University
• Language: English
• Date: 2013-05
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013, Wolters Kluwer Health
• Final Published Version (URL): http://atvb.ahajournals.org/content/33/5/988.long
• Title of Journal or Parent Work: Arteriosclerosis, Thrombosis, and Vascular Biology
• ISSN: 1079-5642
• Volume: 33
• Issue: 5
• Start Page: 988
• End Page: 998
• Grant/Funding Information: This work was funded by grants from NIH UO1 HL80711 and NIH HL60728.
• Keywords: PGC-1α; Angiotensin II; Signal transduction; Vascular senescence
• Research Categories: Health Sciences, General; Biology, General

Abstract

Objective Cellular senescence influences organismal aging and increases predisposition to age-related diseases, in particular cardiovascular disease, a leading cause of death and disability worldwide. PGC-1α is a master regulator of mitochondrial biogenesis and function, oxidative stress and insulin resistance. Senescence is associated with telomere and mitochondrial dysfunction and oxidative stress, inferring a potential causal role of PGC-1α in senescence pathogenesis. Methods and Results We generated a PGC-1α+/−/ApoE−/− mouse model and show that PGC-1α deficiency promotes a vascular senescence phenotype that is associated with increased oxidative stress, mitochondrial abnormalities, and reduced telomerase activity. PGC-1α disruption results in reduced expression of the longevity-related deacetylase sirtuin 1 (SIRT1) and the antioxidant catalase, and increased expression of the senescence marker p53 in aortas. Further, angiotensin II (Ang II), a major hormonal inducer of vascular senescence, induces prolonged lysine acetylation of PGC-1α and releases the PGC-1α·FoxO1 complex from the SIRT1 promoter, thus reducing SIRT1 expression. The phosphorylation defective mutant PGC-1α S570A is not acetylated, is constitutively active for FoxO1-dependent SIRT1 transcription and prevents Ang II-induced senescence. Acetylation of PGC-1α by Ang II interrupts the PGC-1α-FoxO1-SIRT1 feed-forward signaling circuit leading to SIRT1 and catalase downregulation and vascular senescence. Conclusions PGC-1α is a primary negative regulator of vascular senescence. Moreover, the central role of post-translational modification of PGC-1α in regulating Ang II-induced vascular senescence may inform development of novel therapeutic strategies for mitigating age-associated diseases such as atherosclerosis.