Histone acetyltransferase activity of p300 is required for the promotion of left ventricular remodeling after myocardial infarction in adult mice in vivo
Histone acetyltransferase activity of p300 is required for the promotion of left ventricular remodeling after myocardial infarction in adult mice in vivo
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DOI：
10.1161/circulationaha.105.585182
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发表时间：
2006-02-07
期刊：
影响因子：
37.8
通讯作者：
Hasegawa, K
中科院分区：
文献类型：
--
作者：
Miyamoto, S;Kawamura, T;Hasegawa, K
背景-心肌梗死后左心室重构与存活心肌细胞肥大有关，是导致心力衰竭的主要过程。内源性组蛋白乙酰转移酶p300是肥大反应性转录因子如心脏锌指蛋白加塔-4的共激活因子，参与肥大刺激诱导的乙酰化和DNA结合。然而，p300-组蛋白乙酰转移酶活性在体内心肌梗死后左室重塑中的作用是unknow.Methods和Results -为了解决这个问题，我们已经产生了过表达完整的p300或突变的p300在心脏的转基因小鼠。由于其在p300-组蛋白乙酰转移酶结构域中的2-氨基酸取代，该突变体失去了其组蛋白乙酰转移酶活性，并且不能激活加塔-4依赖性转录。两种转基因小鼠和野生型小鼠在12周龄时进行心肌梗死或假手术。与野生型小鼠相比，完整的p300转基因小鼠在心肌梗死后表现出明显更多的进行性LV扩张和收缩功能下降，而突变型p300转基因小鼠没有显示出这一点。结论-这些研究结果表明，心脏过度表达p300促进左心室重塑后心肌梗死在成年小鼠体内，组蛋白乙酰转移酶活性的p300是需要这些过程。
Background - Left ventricular (LV) remodeling after myocardial infarction is associated with hypertrophy of surviving myocytes and represents a major process that leads to heart failure. One of the intrinsic histone acetyltransferases, p300, serves as a coactivator of hypertrophy-responsive transcriptional factors such as a cardiac zinc finger protein GATA-4 and is involved in its hypertrophic stimulus-induced acetylation and DNA binding. However, the role of p300-histone acetyltransferase activity in LV remodeling after myocardial infarction in vivo is unknown.Methods and Results - To solve this problem, we have generated transgenic mice overexpressing intact p300 or mutant p300 in the heart. As the result of its 2-amino acid substitution in the p300-histone acetyltransferase domain, this mutant lost its histone acetyltransferase activity and was unable to activate GATA-4-dependent transcription. The two kinds of transgenic mice and the wild-type mice were subjected to myocardial infarction or sham operation at the age of 12 weeks. Intact p300 transgenic mice showed significantly more progressive LV dilation and diminished systolic function after myocardial infarction than wild-type mice, whereas mutant p300 transgenic mice did not show this.Conclusions - These findings demonstrate that cardiac overexpression of p300 promotes LV remodeling after myocardial infarction in adult mice in vivo and that histone acetyltransferase activity of p300 is required for these processes.