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Author Notes:

To whom correspondence should be addressed: Division of Cardiology, Emory University Hospital, Suite H-153, 1364 Clifton Rd. NE, Atlanta, GA 30322. Tel.: 404-727-1749; Fax: 404-727-3099; E-mail: ralexan@emory.edu.

Present address: Cardiovascular Research Institute, Morehouse School of Medicine, 720 Westview Dr., Atlanta, GA 30310.

We are grateful to Dr. Morris J. Birnbaum for providing adeno-PGC-1α and S570A constructs and Dr. Daniel P. Kelly for providing PGC-1α antibody.

We especially thank Drs. Kathy K. Griendling, David G. Harrison, and Hanjoong Jo for many helpful comments and discussions.

Research Funding:

This work was supported, in whole or in part, by National Institutes of Health Grants UO1 HL80711 and HL60728.

Keywords:

  • Gene/Regulation
  • Hormones
  • Protein/Post-translational Modification
  • Tissue/Organ Systems/Muscle/Smooth
  • Transcription/Coactivators
  • Antioxidants
  • ROS
  • hypertrophy

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

Tools:

Journal Title:

Journal of Biological Chemistry

Volume:

Volume 285, Number 4

Publisher:

, Pages 2474-2487

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

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