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(Circulation Research. 2009;105:746.)
© 2009 American Heart Association, Inc.

Molecular Medicine

p300 Plays a Critical Role in Maintaining Cardiac Mitochondrial Function and Cell Survival in Postnatal Hearts

Yasuaki Nakagawa, Koichiro Kuwahara, Genzo Takemura, Masaharu Akao, Masashi Kato, Yuji Arai, Makoto Takano, Masaki Harada, Masao Murakami, Michio Nakanishi, Satoru Usami, Shinji Yasuno, Hideyuki Kinoshita, Masataka Fujiwara, Kenji Ueshima, Kazuwa Nakao

From the Department of Medicine and Clinical Science (Y.N., K.K., M.H., M.M., M.N., S.U., S.Y., H.K., M.F., K.N.), Department of Cardiovascular Medicine (M.A., M.K.), and EBM Research Center (K.U.), Kyoto University Graduate School of Medicine; Department of Cardiology and Respirology, Regeneration and Advanced Medical Sciences (G.T.), Graduate School of Medicine, Gifu University; Department of Bioscience (Y.A.), National Cardiovascular Center Research Institute, Suita; and Department of Biophysics (M.T.), Jichi Medical School, Shimotsuke, Japan.

Correspondence to Koichiro Kuwahara, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54, Shogoin-Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail kuwa{at}kuhp.kyoto-u.ac.jp

Rationale: It is known that the transcriptional coactivator p300 is crucially involved in the differentiation and growth of cardiac myocytes during development. However, the physiological function of p300 in the postnatal hearts remains to be characterized.

Objective: We have now investigated the physiological function of p300 in adult hearts.

Methods and Results: We analyzed transgenic mice exhibiting cardiac-specific overexpression of a dominant-negative p300 mutant lacking the C/H3 domain (p300C/H3 transgenic [TG] mice). p300C/H3 significantly inhibited p300-induced activation of GATA- and myocyte enhancer factor 2-dependent promoters in cultured ventricular myocytes, and p300C/H3-TG mice showed cardiac dysfunction that was lethal by 20 weeks of age. The numbers of mitochondria in p300C/H3-TG myocytes were markedly increased, but the mitochondria were diminished in size. Moreover, cardiac mitochondrial gene expression, mitochondrial membrane potential and ATP contents were all significantly disrupted in p300C/H3-TG hearts, suggesting that mitochondrial dysfunction contributes to the progression of the observed cardiomyopathy. Transcription of peroxisome proliferator-activated receptor coactivator (PGC)-1, a master regulator of mitochondrial gene expression, and its target genes was significantly downregulated in p300C/H3-TG mice, and p300C/H3 directly repressed myocyte enhancer factor 2C-dependent PGC-1 promoter activity and disrupted the transcriptional activity of PGC-1 in cultured ventricular myocytes. In addition, myocytes showing features of autophagy were observed in p300C/H3-TG hearts.

Conclusions: Collectively, our findings suggest that p300 is essential for the maintenance of mitochondrial integrity and for myocyte survival in the postnatal left ventricular myocardium.

Key Words: mitochondrial function • autophagy • transcription • cardiac dysfunction