p300 Plays a Critical Role in Maintaining Cardiac Mitochondrial Function and Cell Survival in Postnatal Hearts
p300 Plays a Critical Role in Maintaining Cardiac Mitochondrial Function and Cell Survival in Postnatal Hearts
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DOI：
10.1161/circresaha.109.206037
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发表时间：
2009-10-09
影响因子：
20.1
通讯作者：
Nakao, Kazuwa
中科院分区：
文献类型：
--
作者：
Nakagawa, Yasuaki;Kuwahara, Koichiro;Nakao, Kazuwa
基本原理：已知转录辅激活因子p300在发育过程中对心肌细胞的分化和生长起关键作用。然而，p300在出生后的心脏的生理功能仍有待characteristic.Objective：我们现在已经调查了p300在成人hearts.Methods和结果的生理功能：我们分析了转基因小鼠表现出心脏特异性过表达的显性负性p300突变缺乏C/H3域（p300三角洲C/H3转基因[TG]小鼠）。p300 Delta C/H3显著抑制p300诱导的培养的心室肌细胞中GATA和肌细胞增强因子2依赖性启动子的激活，并且p300 Delta C/H3-TG小鼠在20周龄时表现出致命的心功能不全。p300 Δ C/H3-TG心肌细胞线粒体数量明显增多，但体积缩小。此外，心肌线粒体基因表达，线粒体膜电位和ATP含量都显着破坏p300 Δ C/H3-TG心脏，表明线粒体功能障碍有助于所观察到的心肌病的进展。在p300 Delta C/H3-TG小鼠中，过氧化物酶体增殖物激活受体γ共激活因子（PGC）-1 α（线粒体基因表达的主要调节因子）及其靶基因的转录显著下调，p300 Delta C/H3直接抑制了培养的心室肌细胞中肌细胞增强因子2C依赖性PGC-1 α启动子活性，并破坏了PGC-1 α的转录活性。此外，在p300三角洲C/H3-TG hearts.Conclusions：总的来说，我们的研究结果表明，p300是必不可少的线粒体的完整性和心肌细胞的生存在出生后的左心室心肌的维护。(Circ Res. 2009; 105：746-754）。
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.)