Regulation of Cardiac Signaling by Class I Histone Deacetylases

项目摘要/摘要 据估计，在美国约500万心力衰竭(HF)患者中，有一半患有 射血分数保留的心衰，也称为舒张性心力衰竭。高血压 是HFpEF发生的主要危险因素。不幸的是，大型临床试验显示 标准护理HF药物未能降低HFpEF患者的住院率或延长患者的寿命。 因此，HFpEF仍然是一个主要的未得到满足的医疗需求。我们小组长期以来一直有兴趣澄清 被称为组蛋白脱乙酰酶(HDAC)的一系列酶的心脏功能，这些酶起着关键作用，如 基因表达的表观遗传调节器。我们的初步数据显示，一个小的 分子HDAC抑制剂预防和逆转系统性红斑狼疮动物模型舒张性心功能不全 高血压。令人惊讶的是，抑制HDAC似乎通过增强心脏的舒张性功能来改善心脏的舒张功能 收缩单位(肌原纤维)的松弛，揭示了HDAC的非规范、非表观遗传功能 心脏松弛的控制。三个独立的具体目标旨在显著扩展这一新的 心脏研究领域，并检验HDAC非基因组行为支配的总体假设 心脏松弛，并在HFpEF的发病机制中起关键作用。

Project Summary/Abstract It is estimated that half of the ~5 million patients in the United States who suffer from heart failure (HF) have HF with preserved ejection fraction (HFpEF), which is also referred to as diastolic heart failure. Hypertension is a major risk factor for the development of HFpEF. Unfortunately, large clinical trials have revealed that standard-of-care HF medications fail to reduce hospitalization rates or improve lifespan in patients with HFpEF. Thus, HFpEF remains a major unmet medical need. Our group has a longstanding interest in elucidating the cardiac functions of a family of enzymes known as histone deacetylases (HDACs), which serve crucial roles as epigenetic regulators of gene expression. Our preliminary data demonstrate remarkable ability of a small molecule HDAC inhibitor to prevent and reverse diastolic cardiac dysfunction in rodent models of systemic hypertension. Surprisingly, HDAC inhibition appears to improve diastolic function of the heart by enhancing relaxation of the contractile units (myofibrils), revealing a non-canonical, non-epigenetic function for HDACs in the control of cardiac relaxation. Three independent specific aims are designed to significantly extend this new field of cardiac research, and test the overall hypothesis that non-genomic actions of HDACs govern relaxation of the heart, and are critically involved in the pathogenesis of HFpEF.