HDAC Inhibition in Cardiac Hypertrophy and Failure

最近的研究指出了控制组蛋白乙酰化的酶作为应激的重要性- 心脏基因表达的反应调节器。这些酶作为核整合剂发挥作用， 偶联不同的上游信号以控制基因表达。组蛋白的药理学抑制 脱乙酰酶（HDAC）作为肿瘤学领域中有前景的治疗方法正在兴起。在这 因此，我们将探索HDAC抑制作为心脏病的新疗法。 抑制HDAC活性可减弱培养心肌细胞的肥大生长。初步 我们实验室使用2种广谱HDAC抑制剂的结果证明了对肥大的显著抑制 在临床相关的主动脉结扎模型中。重要的是，尽管后负荷应激持续存在，HDAC 对于肥厚性生长，通道介导的钝化作用耐受良好，心室大小和收缩压 性能得到保留，间质纤维化减少。因此，HDAC抑制（HDACi） 似乎能抑制心脏的病理性生长我们假设HDAC抑制与这些（和 其他）小分子可能是心脏病的重要治疗方法，值得进一步研究。 调查在这里，我们建议在压力超负荷肥大和衰竭的动物模型中进行研究， 旨在确定HDAC抑制疗法的效用。在目标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，并检查其普遍性 抗肥大治疗的方法。在目标2中，我们将研究选定的分子机制， 假设有助于HDACi的有益作用，特别是1）增强Foxo活性，和2） 抑制MHC同种型转换。在目标3中，提出了研究来定义分子机制， 保护收缩性能，包括细胞内Ca 2+稳态和表达的变化， 参与Ca 2+处理的蛋白质的磷酸化。在目标4中，我们将破译 减少HDAC抑制剂治疗的心脏中的纤维化，测试HDAC抑制剂对 在培养的心脏成纤维细胞和体内胶原的生物合成和加工。 这里提出的研究将探讨我们的初步研究中观察到的HDAC抑制剂的3个主要作用。 压力应激心肌的研究：衰减肥大生长，保留收缩性能， 和减少纤维化。总之，这些研究将提供重要的见解， HDACi药物治疗作为一种新的抗肥大策略。

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 hypotheisze 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.