Kook Hyun, Lepore John J, Gitler Aaron D, Lu Min Min, Wing-Man Yung Wendy, Mackay Joel, Zhou Rong, Ferrari Victor, Gruber Peter, Epstein Jonathan A
Cardiovascular Division, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA.
J Clin Invest. 2003 Sep;112(6):863-71. doi: 10.1172/JCI19137.
Activation of multiple pathways is associated with cardiac hypertrophy and heart failure. Repression of antihypertrophic pathways has rarely been demonstrated to cause cardiac hypertrophy in vivo. Hop is an unusual homeodomain protein that is expressed by embryonic and postnatal cardiac myocytes. Unlike other homeodomain proteins, Hop does not bind DNA. Rather, it modulates cardiac growth and proliferation by inhibiting the transcriptional activity of serum response factor (SRF) in cardiomyocytes. Here we show that Hop can inhibit SRF-dependent transcriptional activation by recruiting histone deacetylase (HDAC) activity and can form a complex that includes HDAC2. Transgenic mice that overexpress Hop develop severe cardiac hypertrophy, cardiac fibrosis, and premature death. A mutant form of Hop, which does not recruit HDAC activity, does not induce hypertrophy. Treatment of Hop transgenic mice with trichostatin A, an HDAC inhibitor, prevents hypertrophy. In addition, trichostatin A also attenuates hypertrophy induced by infusion of isoproterenol. Thus, chromatin remodeling and repression of otherwise active transcriptional processes can result in hypertrophy and heart failure, and this process can be blocked with chemical HDAC inhibitors.
多种信号通路的激活与心肌肥厚和心力衰竭相关。抗肥厚信号通路的抑制在体内很少被证明会导致心肌肥厚。Hop是一种特殊的同源结构域蛋白，在胚胎期和出生后的心肌细胞中表达。与其他同源结构域蛋白不同，Hop不与DNA结合。相反，它通过抑制心肌细胞中血清反应因子（SRF）的转录活性来调节心脏的生长和增殖。在这里，我们表明Hop可以通过募集组蛋白去乙酰化酶（HDAC）活性来抑制SRF依赖的转录激活，并且可以形成一个包含HDAC2的复合物。过表达Hop的转基因小鼠会出现严重的心肌肥厚、心脏纤维化和过早死亡。一种不募集HDAC活性的Hop突变体不会诱导心肌肥厚。用HDAC抑制剂曲古抑菌素A治疗Hop转基因小鼠可预防心肌肥厚。此外，曲古抑菌素A还可减轻异丙肾上腺素输注诱导的心肌肥厚。因此，染色质重塑和对原本活跃的转录过程的抑制可导致心肌肥厚和心力衰竭，并且这个过程可以被化学HDAC抑制剂阻断。
