Quantitative control of adaptive cardiac hypertrophy by acetyltransferase p300.
Quantitative control of adaptive cardiac hypertrophy by acetyltransferase p300.
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DOI：
10.1161/circulationaha.107.760488
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发表时间：
2008-08-26
期刊：
影响因子：
37.8
通讯作者：
Bishopric NH
中科院分区：
文献类型：
--
作者：
Wei JQ;Shehadeh LA;Mitrani JM;Pessanha M;Slepak TI;Webster KA;Bishopric NH
乙酰转移酶p300是心脏发育所必需的，并且被认为通过MEF 2和GATA 4依赖性转录参与心肌细胞生长。然而，p300在体内心脏生长调节中的重要性尚不清楚。由横主动脉缩窄、出生后生理性生长和人类心力衰竭引起的压力超负荷与p300的大幅增加相关。p300的最小转基因过表达（1.5-3.5倍）诱导显著的心肌细胞和心脏肥大。死亡率和心脏质量与p300蛋白剂量直接相关。单个p300等位基因的杂合性丢失使压力超负荷诱导的肥大减少约50%，并挽救了p300过表达者的肥大表型。p300表达增加对总组蛋白脱乙酰酶活性没有影响，但与p300乙酰转移酶活性和p300底物组蛋白3和加塔-4的乙酰化成比例增加相关。值得注意的是，p300水平的加倍与MEF 2的从头乙酰化有关。与此相一致，在p300 tg心脏中特异性上调的基因高度富集MEF 2结合位点。p300的小增量是必要的，足以驱动心肌肥大，可能通过MEF 2的乙酰化，和上游的信号促进磷酸化或HDAC的核输出。我们建议，诱导心肌p300含量是一个主要的，限速事件在体内的血流动力学负荷的反应和p300的可用性驱动和约束适应性心肌生长。特异性降低p300的含量或活性可以减少应激诱导的心肌肥厚，并阻止心力衰竭的发展。
Acetyltransferase p300 is essential for cardiac development, and is thought to be involved in cardiac myocyte growth through MEF2 and GATA4-dependent transcription. However, the importance of p300 in the modulation of cardiac growth in vivo is unknown. Pressure overload induced by transverse aortic coarctation, postnatal physiologic growth and human heart failure were associated with large increases in p300. Minimal transgenic overexpression of p300 (1.5–3.5-fold) induced striking myocyte and cardiac hypertrophy. Both mortality and cardiac mass were directly related to p300 protein dosage. Heterozygous loss of a single p300 allele reduced pressure overload-induced hypertrophy by ~50%, and rescued the hypertrophic phenotype of p300 overexpressors. Increased p300 expression had no effect on total histone deacetylase activity, but was associated with proportional increases in p300 acetyltransferase activity and acetylation of p300 substrates histone 3 and GATA-4. Remarkably, a doubling of p300 levels was associated with the de novo acetylation of MEF2. Consistent with this, genes specifically upregulated in p300tg hearts were highly enriched for MEF2 binding sites. Small increments in p300 are necessary and sufficient to drive myocardial hypertrophy, possibly through acetylation of MEF2, and upstream of signals promoting phosphorylation or nuclear export of HDACs. We propose that induction of myocardial p300 content is a primary, rate-limiting event in the response to hemodynamic loading in vivo and that p300 availability drives and constrains adaptive myocardial growth. Specific reduction of p300 content or activity may diminish stress-induced hypertrophy and forestall the development of heart failure.