Abstract 987: Functional Inhibition Of p300 Leads To Mitochondrial Dysfunction And Autophagic Myocardial Cell Death In The Adult Heart
p300 is one of transcriptional co-activators fundamentally important in various signal-modulated transcriptional events. It was shown that the cardiac specific overexpression of p300 developed heart failure in adult mice. On the other hand, in embryonic stage p300 has been shown to be essential for cardiac development. In this study, to evaluate the physiological role of p300 in the adult heart, we analyzed the mice carrying cardiac specific overexpression of dominant-negative mutant of p300 (C/H3 domain deletion mutant of p300; DN-p300). DN-p300 transgenic mice(TG) showed the significantly reduced survival rate compared to non-transgenic mice(NTG) and mostly died by 20 weeks of age At 12 weeks, TG showed the significant increase in the heart or lung weight-to-body weight ratio (P < 0.01). In echocardiography, TG revealed the depressed ejection fraction (NTG [n = 8],65.5Â ± 1.5%; TG [n = 11], 33.1Â ± 2.6%; P < 0.01) and the increased LV end-systolic diameter (NTG [n = 8], 4.3Â ± 0.12 mm; TG [n = 11], 5.26Â ± 0.11 mm; P < 0.01), but no significant difference in the wall thickness of the left ventricles. Histological analysis demonstrated the increased interstitial fibrosis and myofibrillar disarray in the ventricles of TG. In electron microscopic (EM) analysis, we found the markedly increased number and reduced size of mitochondria in TG hearts. Tetramethylrhodamine ethylesters (TMRE) staining revealed the diminished mitochondrial membranous potential in TG. RT-PCR analysis showed that the expression of genes encoding multiple mitochondrial genes and PGC-1alpha, a pivotal master regulator of mitochondrial genes, was significantly decreased in TG. In vitro, DN-p300 suppressed the activity of PGC-1alpha promoter. As mitochondrial dysfunction was known to lead to cell death including apoptosis and autophagy, in TG heart we examined the cell death and found the increase in autophagic degeneration of cardiac myocytes in EM analysis. Consistent with this finding, protein expression of cathepsin D and LC3 was increased in TG. Collectively, all these data indicate the critical role of p300 in the maintanance of mitochondrial gene expression and function, and the myocardial cell survival in post-natal heart.