PGC-1 alpha Serine 570 Phosphorylation and GCN5-mediated Acetylation by Angiotensin II Drive Catalase Down-regulation and Vascular Hypertrophy

• Type of Material: Article
• Authors: ShiQin Xiong, Emory University; Gloria Salazar, Emory University; Alejandra San Martin Almeyda, Emory University; Mushtaq Ahmad, Emory University; Nikolay Patrushev, Emory University; Lu Hilenski, Emory University; Rafal Robert Nazarewicz, Emory University; Minhui Ma, Emory University; Masuko Ushio-Fukai, University of Illinois at Chicago; R Wayne Alexander, Emory University
• Language: English
• Date: 2010-01-22
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://www.jbc.org/content/285/4/2474
• Title of Journal or Parent Work: Journal of Biological Chemistry
• ISSN: 0021-9258
• Volume: 285
• Issue: 4
• Start Page: 2474
• End Page: 2487
• Grant/Funding Information: This work was supported, in whole or in part, by National Institutes of Health Grants UO1 HL80711 and HL60728.
• Keywords: Tissue/Organ Systems/Muscle/Smooth; Gene/Regulation; Protein/Post-translational Modification; Hormones; hypertrophy; Transcription/Coactivators; Antioxidants; ROS

Abstract

Angiotensin II (Ang II) is a pleuripotential hormone that is important in the pathophysiology of multiple conditions including aging, cardiovascular and renal diseases, and insulin resistance. Reactive oxygen species (ROS) are important mediators of Ang II-induced signaling generally and have a well defined role in vascular hypertrophy, which is inhibited by overexpression of catalase, inferring a specific role of H2O2. The molecular mechanisms are understood incompletely. The transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a key regulator of energy metabolism and ROS-scavenging enzymes including catalase. We show that Ang II stimulates Akt-dependent PGC-1α serine 570 phosphorylation, which is required for the binding of the histone acetyltransferase GCN5 (general control nonderepressible 5) to PGC-1α and for its lysine acetylation. These sequential post-translational modifications suppress PGC-1α activity and prevent its binding to the catalase promoter through the forkhead box O1 transcription factor, thus decreasing catalase expression. We demonstrate that overexpression of the phosphorylation-defective mutant PGC-1α (S570A) prevents Ang II-induced increases in H2O2 levels and hypertrophy ([3H]leucine incorporation). Knockdown of PGC-1α by small interfering RNA promotes basal and Ang II-stimulated ROS and hypertrophy, which is reversed by polyethylene glycol-conjugated catalase. Thus, endogenous PGC-1α is a negative regulator of vascular hypertrophy by up-regulating catalase expression and thus reducing ROS levels. We provide novel mechanistic insights by which Ang II may mediate its ROS-dependent pathophysiologic effects on multiple cardiometabolic diseases.