P300 Plays a Critical Role in Maintaining Cardiac Mitochondrial Function and Cell Survival in Postnatal Hearts

Abstract

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. We have now investigated the physiological function of p300 in adult hearts. We analyzed transgenic mice exhibiting cardiac-specific overexpression of a dominant-negative p300 mutant lacking the C/H3 domain (p300DeltaC/H3 transgenic [TG] mice). p300DeltaC/H3 significantly inhibited p300-induced activation of GATA- and myocyte enhancer factor 2-dependent promoters in cultured ventricular myocytes, and p300DeltaC/H3-TG mice showed cardiac dysfunction that was lethal by 20 weeks of age. The numbers of mitochondria in p300DeltaC/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 p300DeltaC/H3-TG hearts, suggesting that mitochondrial dysfunction contributes to the progression of the observed cardiomyopathy. Transcription of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha, a master regulator of mitochondrial gene expression, and its target genes was significantly downregulated in p300DeltaC/H3-TG mice, and p300DeltaC/H3 directly repressed myocyte enhancer factor 2C-dependent PGC-1alpha promoter activity and disrupted the transcriptional activity of PGC-1alpha in cultured ventricular myocytes. In addition, myocytes showing features of autophagy were observed in p300DeltaC/H3-TG hearts. Collectively, our findings suggest that p300 is essential for the maintenance of mitochondrial integrity and for myocyte survival in the postnatal left ventricular myocardium.