RGD Reference Report - PGC-1 alpha serine 570 phosphorylation and GCN5-mediated acetylation by angiotensin II drive catalase down-regulation and vascular hypertrophy. - Rat Genome Database

RGD Reference Report - PGC-1 alpha serine 570 phosphorylation and GCN5-mediated acetylation by angiotensin II drive catalase down-regulation and vascular hypertrophy. - Rat Genome Database

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General

PGC-1 alpha serine 570 phosphorylation and GCN5-mediated acetylation by angiotensin II drive catalase down-regulation and vascular hypertrophy.
Authors:	Xiong, S Salazar, G San Martin, A Ahmad, M Patrushev, N Hilenski, L Nazarewicz, RR Ma, M Ushio-Fukai, M Alexander, RW
Citation:	Xiong S, etal., J Biol Chem. 2010 Jan 22;285(4):2474-87. doi: 10.1074/jbc.M109.065235. Epub 2009 Nov 23.
RGD ID:	8693747
Pubmed:	PMID:19940161 (View Abstract at PubMed)
PMCID:	PMC2807304 (View Article at PubMed Central)
DOI:	DOI:10.1074/jbc.M109.065235 (Journal Full-text)
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.

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Molecular Function

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Kat2a	Rat	protein binding		IPI	Ppargc1a (Rattus norvegicus)		RGD
Ppargc1a	Rat	protein binding		IPI	Kat2a (Rattus norvegicus)		RGD

Objects Annotated

Genes (Rattus norvegicus)

Kat2a (lysine acetyltransferase 2A)

Ppargc1a (PPARG coactivator 1 alpha)

Additional Information