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)的一个子集，I类HDAC，在控制舒张性心力衰竭中的作用。在美国，每年有超过60万例心力衰竭(HF)被诊断出来，加上500多万患有这种疾病的成年人；每年的护理费用估计为348亿美元。这些患者中约有一半患有心力衰竭，并保留射血分数(HFpEF)，或舒张性心力衰竭。老龄化和高血压是老年高血压的主要危险因素。 高频脉冲电场的发展。在过去的二十年里，收缩性心力衰竭(SHF)患者通过药物治疗已经看到了临床上的好处；不幸的是，标准护理SHF药物未能在HFpEF患者的大型临床试验中显示出疗效。组蛋白脱乙酰酶(HDAC)催化从多种蛋白质的赖氨酸残基中去除乙酰基。18种哺乳动物的HDAC由不同的基因编码，分为四类(I、II、III和IV)。HDAC催化活性的广谱‘PAN’抑制剂在癌症市场上很受欢迎。我们的初步数据表明，在慢性高血压诱导的HFpEF啮齿动物模型中，PAN-HDAC抑制具有深刻的保护作用。HDAC抑制可阻止心肌肥大和纤维化，改善舒张心功能，并延长生命，即使面对持续的高血压。在随后的研究中，我们确定了I类HDAC选择性抑制通过与诱导抗炎调节T细胞(Tregs)相关的机制来阻断心脏纤维化。这些结果表明，异构体选择性HDAC抑制剂在治疗人HFpEF方面有意想不到的应用。这项建议旨在解决I类HDAC通过触发心室炎症和纤维化而促进老化心脏舒张期功能障碍的总体假设。这些研究的结果将为舒张性心力衰竭的分子基础提供新的见解，并可能为基于异构体选择性HDAC抑制的HFpEF药物开发的创新方法奠定基础。 与公共健康相关：心力衰竭是一个主要的健康问题，也是世界范围内日益增长的经济负担。仅在美国就有500多万心力衰竭患者，这种疾病的治疗每年给美国医疗保健系统带来的成本估计超过370亿美元。这项提案中概述的研究应该为发现治疗老年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.