Cardiac p300 Is Involved in Myocyte Growth with Decompensated Heart Failure

Abstract

A variety of stresses on the heart initiate a number of subcellular signaling pathways, which finally reach the nuclei of cardiac myocytes and cause myocyte hypertrophy with heart failure. However, common nuclear pathways that lead to this state are unknown. A zinc finger protein, GATA-4, is one of the transcription factors that mediate changes in gene expression during myocardial-cell hypertrophy. p300 not only acts as a transcriptional coactivator of GATA-4, but also possesses an intrinsic histone acetyltransferase activity. In primary cardiac myocytes derived from neonatal rats, we show that stimulation with phenylephrine increased an acetylated form of GATA-4 and its DNA-binding activity, as well as expression of p300. A dominant-negative mutant of p300 suppressed phenylephrine-induced nuclear acetylation, activation of GATA-4-dependent endothelin-1 promoters, and hypertrophic responses, such as increase in cell size and sarcomere organization. In sharp contrast to the activation of cardiac MEK-1, which phosphorylates GATA-4 and causes compensated hypertrophy in vivo, p300-mediated acetylation of mouse cardiac nuclear proteins, including GATA-4, results in marked eccentric dilatation and systolic dysfunction. These findings suggest that p300-mediated nuclear acetylation plays a critical role in the development of myocyte hypertrophy and represents a pathway that leads to decompensated heart failure.Heart failure arises from a number of diverse primary cardiovascular disorders and is associated with significant morbidity and mortality. Therefore, elucidating the mechanisms of this disease is of clinical importance. Previous studies have demonstrated that a variety of stresses on the heart activate neuronal and hormonal factors, such as the renin-angiotensin system and factors regulating the sympathetic nervous systems. These factors initiate a number of subcellular signaling pathways, which finally reach the nuclei of cardiac myocytes and change the pattern of gene expression associated with hypertrophy (reviewed in references 14 and 53). In order to establish appropriate therapy for heart failure, it is critical to identify a common nuclear pathway which can be targeted by pharmacological agents in the future.We have been interested in transcription factors that mediate changes in gene expression during myocardial-cell hypertrophy. A zinc finger protein, GATA-4, is one such factor and is required for transcriptional activation of cardiac genes whose expression is upregulated during myocardial-cell hypertrophy (22, 25; reviewed in reference 46). While overexpression of GATA-4 in cardiac myocytes causes hypertrophy, expression of a dominant-negative form of GATA-4 inhibits Gq protein-coupled receptor agonist-induced hypertrophy (37). During myocardial-cell hypertrophy, GATA-4 is phosphorylated at a serine residue and shows increased DNA-binding ability (38,47). Phosphorylation of cardiac GATA-4 requires activation of MEK1/extracellular signal-regulated kinase (ERK) 1/2. On the other hand, activation of MEK1 in...

Inhibition of Cardiomyocyte Hypertrophy by Protein Arginine Methyltransferase 5

“…In response to hypertrophic stimuli, such as endothelin-1, PE, and isoproterenol, GATA4 is phosphorylated at Ser-105 by the MAPK pathway, which in turn enhances its transcriptional activity and promotes cardiomyocyte hypertrophy (34). In addition, GATA4 is subjected to the lysine modifications via acetylation and sumoylation (10,11). 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).…”

“…PRMT5 Negatively Regulates GATA4 Activity-GATA4 has been shown to regulate expression of various cardiac genes, such as ANF and BNP, and its activity can be potentiated by p300 mediated acetylation (10). Thus, we sought to determine whether PRMT5 affects the transcriptional activity of GATA4.…”

“…In contrast, phosphorylation of GATA4 by glycogen synthase kinase 3␤ leads to nuclear exit of GATA4, thus suppressing GATA4 transcriptional activity and induction of cardiac hypertrophy (9). GATA4 activity is also influenced by other post-translational modifications, such as acetylation (10), sumoylation (11), and methylation (12). Specifically, p300 has been shown to interact with GATA4 and potentiate its transcriptional activity through acetylation (10).…”

“…GATA4 activity is also influenced by other post-translational modifications, such as acetylation (10), sumoylation (11), and methylation (12). Specifically, p300 has been shown to interact with GATA4 and potentiate its transcriptional activity through acetylation (10). Relevant to this, polycomb-repressive complex 2 (PRC2), a histone methyltransferase, has been shown to directly methylate GATA4 at lysine 299, which results in an inhibition of GATA4 transcriptional activity (12).…”

Acetylation of GATA-4 Is Involved in the Differentiation of Embryonic Stem Cells into Cardiac Myocytes

“…For example, p300 acetylates p53, increases its DNA binding activity, and activates the transcription of p53-inducible genes, contributing to cell cycle arrest or apoptosis (6,7). In cardiac myocytes, p300 acetylates GATA-4, enhances its DNA binding, and plays an important role in the transactivation of hypertrophy-responsive genes (8). However, the roles of HATs and HDACs in post-translational modification of GATA-4 during the differentiation of ES cells into cardiac myocytes remain unknown.…”