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(Circulation. 2006;113:679-690.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

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

Shoichi Miyamoto, MD^*; Teruhisa Kawamura, MD, PhD^*; Tatsuya Morimoto, MD, PhD; Koh Ono, MD, PhD; Hiromichi Wada, MD, PhD; Yosuke Kawase, PhD; Akira Matsumori, MD, PhD; Ryosuke Nishio, MD, PhD; Toru Kita, MD, PhD; Koji Hasegawa, MD, PhD

From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan (S.M., T.M., A.M., R.N., T. Kita); the Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan (T. Kawamura, K.O., H.W., K.H.); and the Chugai Research Institute for Medical Science, Inc, Pharmacology & Pathology Research Center, Shizuoka, Japan (Y.K.).

Correspondence to Dr Koji Hasegawa, Division of Translational Research, Kyoto Medical Center, National Hospital Organization, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto, 612-8555, Japan. E-mail koj{at}kuhp.kyoto-u.ac.jp

Received April 20, 2005; de novo received August 26, 2005; revision received October 17, 2005; accepted November 22, 2005.

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.

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