Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA.
Trends Cardiovasc Med. 2013 Aug;23(6):229-35. doi: 10.1016/j.tcm.2012.12.006. Epub 2013 Mar 15.
Heart failure, a syndrome culminating the pathogenesis of many forms of heart disease, is highly prevalent and projected to be increasingly so for years to come. Major efforts are directed at identifying the means of preventing, slowing, or possibly reversing the unremitting progression of pathological stress leading to myocardial injury and ultimately heart failure. Indeed, despite widespread use of evidence-based therapies, heart failure morbidity and mortality remain high. Recent work has uncovered a fundamental role of reversible protein acetylation in the regulation of many biological processes, including pathological remodeling of the heart. This reversible acetylation is governed by enzymes that attach (histone acetyltransferases, HATs) or remove (histone deacetylases, HDACs) acetyl groups. In the latter case, small molecule inhibitors of HDACs are currently being tested for a variety of oncological indications. Now, evidence has revealed that HDAC inhibitors blunt pathological cardiac remodeling in the settings of pressure overload and ischemia/reperfusion, thereby diminishing the emergence of heart failure. Mechanistically, HDAC inhibitors reduce stress-induced cardiomyocyte death, hypertrophy, and ventricular fibrosis. Looking to the future, HDAC inhibitor therapy may emerge as a novel means of arresting the untoward consequences of pathological cardiac stress, conferring clinical benefit to millions of patients with heart failure.
心力衰竭是多种类型心脏病发展到终末阶段的一种综合征，其发病率极高，预计未来几年还会进一步上升。目前主要致力于寻找预防、减缓或可能逆转导致心肌损伤并最终导致心力衰竭的持续进行的病理性压力的进展的方法。尽管广泛使用了循证治疗方法，但心力衰竭的发病率和死亡率仍然很高。最近的研究揭示了可逆蛋白质乙酰化在许多生物过程（包括心脏的病理性重塑）中的调节中的基本作用。这种可逆乙酰化受添加（组蛋白乙酰转移酶，HATs）或去除（组蛋白去乙酰化酶，HDACs）乙酰基的酶控制。在后一种情况下，目前正在针对各种肿瘤适应症测试 HDAC 抑制剂的小分子抑制剂。现在，有证据表明，HDAC 抑制剂可减轻压力超负荷和缺血/再灌注情况下的病理性心脏重塑，从而减少心力衰竭的发生。从机制上讲，HDAC 抑制剂可减少应激诱导的心肌细胞死亡、肥大和心室纤维化。展望未来，HDAC 抑制剂治疗可能成为阻止病理性心脏压力不良后果的一种新方法，为数百万心力衰竭患者带来临床获益。
