Histone Acetyltransferase Activity of p300 Is Required for the Promotion of Left Ventricular Remodeling After Myocardial Infarction in Adult Mice In Vivo

Abstract

Background-Left ventricular (LV) remodeling after myocardial infarction is associated with hypertrophy of surviving myocytes and represents a major process that leads to heart failure. One of the intrinsic histone acetyltransferases, p300, serves as a coactivator of hypertrophy-responsive transcriptional factors such as a cardiac zinc finger protein GATA-4 and is involved in its hypertrophic stimulus-induced acetylation and DNA binding. However, the role of p300-histone acetyltransferase activity in LV remodeling after myocardial infarction in vivo is unknown. Methods and Results-To solve this problem, we have generated transgenic mice overexpressing intact p300 or mutant p300 in the heart. As the result of its 2-amino acid substitution in the p300-histone acetyltransferase domain, this mutant lost its histone acetyltransferase activity and was unable to activate GATA-4 -dependent transcription. The two kinds of transgenic mice and the wild-type mice were subjected to myocardial infarction or sham operation at the age of 12 weeks. Intact p300 transgenic mice showed significantly more progressive LV dilation and diminished systolic function after myocardial infarction than wild-type mice, whereas mutant p300 transgenic mice did not show this. Conclusions-These findings demonstrate that cardiac overexpression of p300 promotes LV remodeling after myocardial infarction in adult mice in vivo and that histone acetyltransferase activity of p300 is required for these processes.

Kruppel-like Factor 15 Is a Critical Regulator of Cardiac Lipid Metabolism

“…Previous studies have implicated p300 acetyltransferase as a positive regulator of pathologic cardiomyocyte hypertrophy, possibly via its ability to acetylate prohypertrophic transcription factors, such as GATA4, MEF2, and p53 (21,(47)(48)(49)(50). Prior work from our group has shown that Klf15 expression is dramatically reduced during pathologic cardiac hypertrophy, an event that releases repression of GATA4, MEF2, and the p300-p53 transcriptional module (20,21).…”

Inhibition of Cardiomyocyte Hypertrophy by Protein Arginine Methyltransferase 5

“…Indeed, the transcriptional co-activator p300 interacts with GATA4 and enhances its transcriptional activity by acetylating lysine residues in the C-terminal region (35,36). Furthermore, cardiac overexpression of intact p300 has been shown to induce acetylation of GATA4 and cardiac hypertrophy and promote left ventricular remodeling after myocardial infarction in vivo (37). However, overexpression of mutant p300 lacking HAT (histone acetyltransferase) activity diminishes these effects, suggesting that p300-induced acetylation of GATA4 is required for the development of cardiac hypertrophy (37).…”

“…Furthermore, cardiac overexpression of intact p300 has been shown to induce acetylation of GATA4 and cardiac hypertrophy and promote left ventricular remodeling after myocardial infarction in vivo (37). However, overexpression of mutant p300 lacking HAT (histone acetyltransferase) activity diminishes these effects, suggesting that p300-induced acetylation of GATA4 is required for the development of cardiac hypertrophy (37). At this point the molecular mechanism underlying the regulation of p300-mediated acetylation of GATA4 in the heart has not been clearly elucidated.…”

Regulation of Cardiac Transcription Factor GATA4 by Post-Translational Modification in Cardiomyocyte Hypertrophy and Heart Failure

“…22) Transcriptional coactivator p300 was first identified as an E1A binding protein; it serves as a HAT, a scaffold protein or bridge for transcription factors and other components of the basal transcription machinery to facilitate chromatin remodeling, and it activates gene transcription. Cardiac-specific p300 transgenic mice have shown acceleration of left ventricular remodeling after myocardial infarction, but the acceleration of remodeling in HAT activity-lacking p300 transgenic mice is attenuated, 24,25) indicating that the HAT activity of p300 is necessary for left ventricular remodeling after myocardial infarction. The zinc finger domain of the c-terminus of GATA4 contains some residual lysine groups and plays important roles in the capacity to bind to DNA and to other factors.…”