Cardiac p300 is involved in myocyte growth with decompensated heart failure.
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.
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Tetsuhiko
T
Yanazume
Koji
K
Hasegawa
Tatsuya
T
Morimoto
Teruhisa
T
Kawamura
Hiromichi
H
Wada
Akira
A
Matsumori
Yosuke
Y
Kawase
Maretoshi
M
Hirai
Toru
T
Kita
D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D050881:E1A-Associated p300 Protein; D004452:Echocardiography; D050991:GATA4 Transcription Factor; D006333:Heart Failure / Q000378:metabolism; D007150:Immunohistochemistry; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010656:Phenylephrine / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D051381:Rats; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D010656:Phenylephrine; D004247:DNA; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; C494362:Ep300 protein, rat; D008239:Lysine