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Cardiac p300 is involved in myocyte growth with decompensated heart failure
Tetsuhiko Yanazume1, Koji Hasegawa, Tatsuya Morimoto
1Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Insights
Heart failure involves myocyte hypertrophy. A protein called p300 acetylates GATA-4, a key transcription factor, leading to heart failure. This acetylation pathway drives cardiac dysfunction.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cellular Signaling
Background:
- Heart failure is often preceded by myocyte hypertrophy, a process involving nuclear signaling pathways.
- Transcription factors like GATA-4 regulate gene expression during cardiac hypertrophy.
- p300, a coactivator with histone acetyltransferase activity, interacts with GATA-4.
Purpose of the Study:
- To investigate the role of p300-mediated acetylation in GATA-4 activity and myocyte hypertrophy.
- To determine if p300 acetylation leads to decompensated heart failure.
Main Methods:
- Primary neonatal rat cardiac myocytes were stimulated with phenylephrine.
- GATA-4 acetylation, DNA-binding activity, and p300 expression were assessed.
- Dominant-negative p300 mutants were used to block acetylation and its downstream effects.
Main Results:
- Phenylephrine increased GATA-4 acetylation and p300 expression in cardiac myocytes.
- p300 inhibition blocked phenylephrine-induced GATA-4 activation and hypertrophic responses.
- p300-mediated acetylation of cardiac proteins induced eccentric dilatation and systolic dysfunction, unlike MEK-1 activation.
Conclusions:
- p300-mediated nuclear acetylation is a critical pathway in the development of myocyte hypertrophy.
- This acetylation process promotes decompensated heart failure by inducing cardiac dysfunction.
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.