Deacetylase-Dependent Control of Diastolic Dysfunction and HFpEF

项目总结/摘要 在心力衰竭（HF）患者中使用过量神经激素活性抑制剂的大型临床结局试验， 射血分数（HFrEF）患者的死亡率已显示出显著降低。然而，这些影响 在射血分数保留的HF（HFpEF）患者中， 达到积极的初步结果。患者反应的二分法可能是由于 HFpEF与HFrEF病理生理学的差异，以及缺乏实验HFpEF模型， 捕捉这种综合征的基本特征。我们的论点，以及建议中使用的方法 同时使用大动物HFpEF模型和舒张功能障碍小鼠模型， 保留的EF将使我们能够证明推定的治疗剂对HFpEF表型的共同作用， 从而促进了我们的研究结果在估计的250万目前患有HFpEF的人中的翻译， 美国单独。 在过去的一年里，这两个项目的工作是第一次说明一个家庭的关键作用， 表观遗传调节酶，组蛋白脱乙酰酶（HDAC），在舒张功能障碍的控制和 HFpEF发病机制。麦肯锡实验室表明，一种小分子HDAC抑制剂可以防止 舒张功能不全的大鼠和小鼠模型中的舒张功能不全，具有由 高血压或衰老。引人注目的是，这项工作是第一个将肌原纤维松弛的损伤与 在啮齿类动物以及HFpEF患者中发生舒张功能障碍。此外，还显示， HDAC抑制通过促进肌原纤维蛋白乙酰化改善心脏舒张， 加快肌原纤维松弛速率。豪泽实验室最近也证明了类似的有益效果 HDAC抑制剂在猫模型中的作用，该模型重现了人类HFpEF的许多元素。研究 本申请中提出的将定义一种HDAC抑制策略， 疗效，为HDAC抑制剂在患有以下疾病的患者中进行的概念验证2a期临床试验奠定基础 HFpEF。此外，这项工作将确定哪些HDAC亚型促进舒张功能障碍，并扩大 我们对HDAC抑制剂改善血管舒张的细胞和分子机制的理解， 心脏三个独立的具体目标旨在显着扩展这一新的翻译领域 心脏研究，并测试整体假设，增加HDAC活动有助于 通过调节肌原纤维的蛋白质脱乙酰化促进舒张功能障碍的HFpEF发病机制 松弛、心脏纤维化和/或肌浆网钙摄取。

Project Summary/Abstract Large clinical outcome trials with inhibitors of excess neurohormonal activity in heart failure (HF) with reduced ejection fraction (HFrEF) patients have shown significant decreases in mortality. However, the effects of these same neurohormonal inhibitors in HF with preserved ejection fraction (HFpEF) patients have consistently failed to reach positive primary outcomes. The dichotomy in the responses of the patients likely results from differences in HFpEF versus HFrEF pathophysiology, and the absence of experimental HFpEF models that capture essential characteristics of this syndrome. Our contention, and the approach used in the proposed work, is that concomitant use of a large animal HFpEF model and a mouse model of diastolic dysfunction with preserved EF will enable us to document common effects of a putative therapeutic on the HFpEF phenotype, thus facilitating translation of our findings to the estimated 2.5 million humans currently suffering from HFpEF in the United States alone. Within the last year, work by the two PIs of this proposal was the first to illustrate a crucial role for a family of epigenetic regulatory enzymes, histone deacetylases (HDACs), in the control of diastolic dysfunction and HFpEF pathogenesis. The McKinsey laboratory showed that a small molecule HDAC inhibitor prevented diastolic dysfunction in rat and mouse models of diastolic dysfunction with preserved EF triggered by hypertension or aging. Strikingly, the work was the first to link impairment of myofibril relaxation to the development of diastolic dysfunction in rodents, as well as in humans with HFpEF. Furthermore, it was shown that HDAC inhibition improves relaxation of the heart by promoting myofibrillar protein acetylation, thereby speeding myofibril relaxation rates. The Houser laboratory has recently demonstrated similar beneficial effects of an HDAC inhibitor in a feline model that recapitulates many elements of HFpEF in humans. The studies proposed in this application would define a strategy for HDAC inhibition that provides the greatest therapeutic efficacy, setting the stage for a proof-of-concept Phase 2a clinical trial with an HDAC inhibitor in patients with HFpEF. Furthermore, the work would define which HDAC isoforms promote diastolic dysfunction, and expand our understanding of the cellular and molecular mechanisms by which HDAC inhibitors improve relaxation of the heart. Three independent specific aims are designed to significantly extend this new field of translational cardiac research, and test the overall hypothesis that increased HDAC activity contributes to the pathogenesis of HFpEF by promoting diastolic dysfunction via deacetylation of proteins that regulate myofibril relaxation, cardiac fibrosis and/or sarcoplasmic reticulum calcium uptake.