HDAC Inhibition in Cardiac Hypertrophy and Failure

心脏肥大和衰竭中的 HDAC 抑制

• 批准号: 7212787
• 负责人: JOSEPH A HILL
• 金额: $ 39.25万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-15 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7212787
• 关键词: Actins; Adult; Anabolism; Animal Model; Attention; Attenuated; Biological Preservation; COL1A1 gene; COL1A2 gene; Cardiac; Cardiac Myocytes; Chemosensitization; Chromatin; Class; Clinical; Code; Collagen; Collagen Type I; Data; Elements; End Point; Enzymes; Evaluation; Event; Experimental Designs; Failure; Fibroblasts; Fibrosis; Gene Expression; Genes; Grant; Growth; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; Histones; Homeostasis; Hypertrophy; In Vitro; Investigation; Mediating; Modeling; Molecular; Muscle Cells; Myocardium; Nuclear; Numbers; Performance; Personal Satisfaction; Pharmacotherapy; Phosphorylation; Prevention approach; Process; Protein Isoforms; Research Personnel; Screening procedure; Signal Transduction; Smooth Muscle; Stress; Testing; Therapeutic; Trichostatin A; Ventricular; Ventricular Remodeling; Work; alpha 2 collagen type I; base; chromatin remodeling; clinically relevant; design; fibrogenesis; in vivo; insight; interstitial; mouse model; novel; novel therapeutics; oncology; pressure; programs; research study; response; scriptaid; size; small molecule; tissue culture; type I collagen alpha 1

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.

描述（由申请人提供）：最近的研究指出了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剂的重要性。这些酶作为核整合子发挥作用，耦合不同的上游信号以控制基因表达。组蛋白去乙酰化酶（HDAC）的药理学抑制正在成为肿瘤学领域中一种有前途的治疗方法。在这个提议中，我们将探索HDAC抑制作为心脏病的一种新疗法。抑制HDAC活性可减弱培养心肌细胞的肥大生长。我们实验室使用2种广谱HDAC抑制剂的初步结果证明，在临床相关的主动脉缩窄模型中，肥厚得到显著抑制。重要的是，尽管后负荷应激持续存在，HDAC介导的肥厚性生长钝化耐受良好，心室大小和收缩性能得到保留，间质纤维化减少。因此，HDAC抑制（HDACi）似乎钝化心脏的病理性生长。我们推测，这些（和其他）小分子抑制HDAC可能是心脏病的一种重要治疗方法，值得进一步研究。在这里，我们建议在动物模型的压力超负荷肥大和失败，旨在确定HDAC抑制治疗的效用的研究。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，并检查这种方法的抗肥大治疗的普遍性。在目标2中，我们将检查我们假设有助于HDACi有益作用的选定分子机制，特别是1）增强Foxo活性和2）抑制MHC亚型转换。在目标3中，提出了研究来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。在目标4中，我们将解释HDAC抑制剂治疗心脏中减少纤维化的机制，测试HDAC抑制剂对培养的心脏成纤维细胞和体内胶原蛋白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种主要作用：减弱肥厚性生长、保持收缩性能和减少纤维化。总之，这些研究将提供关于HDACi药物疗法作为一种新型抗肥大策略的效用的重要见解。