PGC-1 alpha serine 570 phosphorylation and GCN5-mediated acetylation by angiotensin II drive catalase down-regulation and vascular hypertrophy.
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 H(2)O(2). The molecular mechanisms are understood incompletely. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) is a key regulator of energy metabolism and ROS-scavenging enzymes including catalase. We show that Ang II stimulates Akt-dependent PGC-1 alpha serine 570 phosphorylation, which is required for the binding of the histone acetyltransferase GCN5 (general control nonderepressible 5) to PGC-1 alpha and for its lysine acetylation. These sequential post-translational modifications suppress PGC-1 alpha 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-1 alpha (S570A) prevents Ang II-induced increases in H(2)O(2) levels and hypertrophy ([(3)H]leucine incorporation). Knockdown of PGC-1 alpha by small interfering RNA promotes basal and Ang II-stimulated ROS and hypertrophy, which is reversed by polyethylene glycol-conjugated catalase. Thus, endogenous PGC-1 alpha 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.
Xiong
Shiqin
S
Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Salazar
Gloria
G
San Martin
Alejandra
A
Ahmad
Mushtaq
M
Patrushev
Nikolay
N
Hilenski
Lula
L
Nazarewicz
Rafal Robert
RR
Ma
Minhui
M
Ushio-Fukai
Masuko
M
Alexander
R Wayne
RW
D000107:Acetylation; D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D002318:Cardiovascular Diseases / Q000378:metabolism* / Q000473:pathology; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006984:Hypertrophy; D008156:Luciferases / Q000235:genetics; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor; D000071161:Forkhead Box Protein O1
D000804:Angiotensin II; D002374:Catalase; D051858:Forkhead Transcription Factors; D008156:Luciferases; D009419:Nerve Tissue Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051057:Proto-Oncogene Proteins c-akt; D016601:RNA-Binding Proteins; D012694:Serine; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C501429:Ppargc1a protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1