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

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 (p300 Delta C/H3 transgenic [TG] mice). p300 Delta C/H3 significantly inhibited p300-induced activation of GATA-and myocyte enhancer factor 2-dependent promoters in cultured ventricular myocytes, and p300 Delta C/H3-TG mice showed cardiac dysfunction that was lethal by 20 weeks of age. The numbers of mitochondria in p300 Delta C/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 p300 Delta C/H3-TG hearts, suggesting that mitochondrial dysfunction contributes to the progression of the observed cardiomyopathy. Transcription of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 alpha, a master regulator of mitochondrial gene expression, and its target genes was significantly downregulated in p300 Delta C/H3-TG mice, and p300 Delta C/H3 directly repressed myocyte enhancer factor 2C-dependent PGC-1 alpha promoter activity and disrupted the transcriptional activity of PGC-1 alpha in cultured ventricular myocytes. In addition, myocytes showing features of autophagy were observed in p300 Delta C/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. (Circ Res. 2009; 105: 746-754.)