Isoform-Selective HDAC Inhibitors for Age-Associated Diastolic Dysfunction

描述（由申请人提供）：本项目的目标是解决组蛋白脱乙酰酶（HDAC）酶的一个子集，I类HDAC在舒张性心力衰竭控制中的作用。在美国，每年诊断出超过60万例心力衰竭（HF）病例，增加了超过500万患有这种疾病的成年人;护理费用估计为每年348亿美元。这些患者中约有一半患有射血分数保留的心力衰竭（HFpEF）或舒张性心力衰竭。老年和高血压是主要的危险因素， HFpEF的发展。在过去的二十年中，收缩性心力衰竭（sHF）患者通过药物管理已经看到了临床获益;不幸的是，标准治疗sHF药物未能在HFpEF患者的大型临床试验中显示疗效。组蛋白脱乙酰酶（HDAC）催化从多种蛋白质中的赖氨酸残基去除乙酰基。18种哺乳动物HDAC由不同的基因编码，并分为四类（I，II，III和IV）。HDAC催化活性的广谱"泛“抑制剂被用于治疗癌症。我们的初步数据表明，泛HDAC抑制在慢性高血压诱导的HFpEF啮齿动物模型中具有深刻的保护作用。HDAC抑制阻断心脏肥大和纤维化，改善舒张期心脏功能，延长寿命，即使在面对持续的高血压。在随后的研究中，我们确定I类HDAC选择性抑制通过与诱导抗炎调节性T细胞（T细胞）相关的机制阻断心脏纤维化。这些结果表明亚型选择性HDAC抑制剂用于治疗人HFpEF的非预期应用。该提案旨在解决I类HDAC通过触发心室炎症和纤维化促进衰老心脏舒张功能障碍的总体假设。这些研究的结果应该为舒张性心力衰竭的分子基础提供新的见解，并且可以形成基于亚型选择性HDAC抑制的HFpEF药物发现的创新方法的基础。 公共卫生相关性：心力衰竭是一个主要的健康问题，也是全球日益增长的经济负担。仅在美国就有超过500万的心力衰竭患者，治疗这种疾病对美国医疗保健系统的估计年度成本超过370亿美元。本提案中概述的研究应为发现治疗年龄相关性心功能不全患者的新疗法提供基础。

DESCRIPTION (provided by applicant): The goal of this project is to address the role of a subset of histone deacetylase (HDAC) enzymes, class I HDACs, in the control of diastolic heart failure. Each year more than 600,000 cases of heart failure (HF) are diagnosed in the United States, adding to the more than 5 million adults with this condition; costs of care are estimated at $34.8 billion per year. About half of these patients have heart failure with preserved ejection fraction (HFpEF), or diastolic heart failure. Aging and hypertension are major risk factors for the development of HFpEF. Over the last two decades, systolic heart failure (sHF) patients have seen clinical benefits through pharmacological management; unfortunately, standard-of-care sHF medications have failed to show efficacy in large clinical trials in patients with HFpEF. Histone deacetylases (HDACs) catalyze removal of acetyl groups from lysine residues in a variety of proteins. The 18 mammalian HDACs are encoded by distinct genes and fall into four classes (I, II, III and IV). Broad-spectrum, 'pan' inhibitors of HDAC catalytic activity are marketd for cancer. Our preliminary data demonstrate that pan-HDAC inhibition is profoundly protective in a rodent model of HFpEF induced by chronic hypertension. HDAC inhibition blocked cardiac hypertrophy and fibrosis, improved diastolic cardiac function, and prolonged lifespan even in the face of sustained hypertension. In subsequent studies we determined that class I HDAC- selective inhibition blocks cardiac fibrosis through a mechanism associated with induction of anti-inflammatory regulatory T cells (Tregs). These results suggest an unanticipated application for isoform-selective HDAC inhibitors for the treatment of human HFpEF. This proposal is designed to address the overall hypothesis that class I HDACs promote diastolic dysfunction in the aging heart by triggering ventricular inflammation and fibrosis. Results from these studies should provide novel insights into the molecular basis of diastolic heart failure, and could form the foundation for innovative approaches to drug discovery for HFpEF based on isoform- selective HDAC inhibition. PUBLIC HEALTH RELEVANCE: Heart failure is a major health problem and growing economic burden worldwide. With greater than five million heart failure patients in the U.S. alone, treatment of this condition represents an estimated annual cost to the American health care system of over $37 billion. The research outlined in this proposal should provide a foundation for discovery of novel therapeutics to treat patient suffering from age-related cardiac dysfunction.