HDAC Inhibition in Cardiac Hypertrophy and Failure

描述（由申请人提供）：最近的研究指出控制组蛋白乙酰化的酶作为心脏中基因表达的应激反应调节因子的重要性。这些酶作为核整合体，将不同的上游信号偶联以控制基因表达。药物抑制组蛋白去乙酰化酶（hdac）正在成为肿瘤领域一种有前途的治疗方法。在这个提议中，我们将探索HDAC抑制作为一种新的治疗心脏病的方法。抑制HDAC活性可抑制培养心肌细胞的肥厚生长。我们实验室使用2种广谱HDAC抑制剂的初步结果显示，在临床相关的主动脉带模型中，肥厚得到了显著抑制。重要的是，尽管持续的负荷后应激，HDAC抑制剂介导的肥厚生长钝化是耐受良好的，心室大小和收缩性能得以保留，间质纤维化减少。因此，HDAC抑制（HDACi）似乎可以抑制心脏的病理性生长。我们假设用这些（和其他）小分子抑制HDAC可能是一种重要的治疗心脏病的方法，值得进一步研究。在这里，我们建议在压力过载肥厚和衰竭的动物模型中进行研究，旨在确定HDAC抑制治疗的效用。在Aim 1中，我们将研究有限数量的结构多样的HDAC抑制剂，以确认和扩展我们的初步研究，确定这些化合物对临床、功能和分子终点的影响，并检查这种方法在抗肥厚治疗中的普遍性。在目标2中，我们将研究我们假设的HDACi有益作用的分子机制，特别是1)增强Foxo活性，2)抑制MHC异构体转换。在Aim 3中，研究提出了定义保持收缩性能的分子机制，包括细胞内Ca2+稳态的变化以及参与Ca2+处理的蛋白质的表达和磷酸化。在Aim 4中，我们将破译HDAC抑制剂治疗心脏纤维化减少的机制，测试HDAC抑制剂对培养的心脏成纤维细胞和体内胶原生物合成和加工的影响。本文提出的研究将探讨我们在压力应激心肌的初步研究中观察到的HDAC抑制剂的3个主要作用：减轻肥厚生长，保持收缩性能，减少纤维生成。总之，这些研究将为HDACi药物治疗作为一种新的抗肥厚策略的效用提供重要的见解。

DESCRIPTION (provided by applicant): Recent studies point to the importance of enzymes that control histone acetylation as stress- responsive regulators of gene expression in the heart. These enzymes function as nuclear integrators that couple diverse upstream signals to govern gene expression. Pharmacological suppression of histone deacetylases (HDACs) is emerging as a promising therapeutic approach in the field of oncology. In this proposal, we will explore HDAC inhibition as a novel therapy in heart disease. Suppression of HDAC activity blunts hypertrophic growth of cardiac myocytes in culture. Preliminary results from our lab with 2 broad-spectrum HDAC inhibitors document significant suppression of hypertrophy in a clinically relevant, aortic banding model. Importantly, despite persistence of afterload stress, HDAC inhibitor-mediated blunting of hypertrophic growth was well tolerated, ventricular size and systolic performance were preserved, and interstitial fibrosis was diminished. Thus, HDAC inhibition (HDACi) appears to blunt pathological growth of the heart. We hypothesize that HDAC suppression with these (and other) small molecules may be an important therapeutic approach in heart disease and worthy of further investigation. Here, we propose studies in animal models of pressure-overload hypertrophy and failure that are designed to determine the utility of HDAC suppressive therapy. In Aim 1, we will study a limited number of structurally diverse HDAC inhibitors to confirm and extend our preliminary studies, determine the effects of these compounds on clinical, functional, and molecular endpoints, and examine the generalizability of this approach to antihypertrophic therapy. In Aim 2, we will examine selected molecular mechanisms we hypothesize contribute to the salutary effects of HDACi, specifically 1) potentiation of Foxo activity, and 2) suppression of MHC isoform switching. In Aim 3, studies are proposed to define molecular mechanisms that preserve systolic performance, including changes in intracellular Ca2+ homeostasis and the expression and phosphorylation of proteins involved in Ca2+ handling. In Aim 4, we will decipher mechanisms governing diminished fibrosis in HDAC inhibitor-treated hearts, testing the effects of HDAC inhibitors on the biosynthesis and processing of collagens in cultured cardiac fibroblasts and in vivo. Studies proposed here will explore the 3 major effects of HDAC inhibitors observed in our preliminary studies of pressure-stressed myocardium: attenuated hypertrophic growth, preserved systolic performance, and diminished fibrogenesis. Together, these studies will provide important insights regarding the utility of HDACi pharmacotherapy as a novel antihypertrophic strategy.