HDAC Inhibition in Cardiac Hypertrophy and Failure

心脏肥大和衰竭中的 HDAC 抑制

• 批准号: 7539918
• 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/7539918
• 关键词: Actins; Adult; Anabolism; Animal Model; Attention; Attenuated; Biological Preservation; COL1A1 gene; COL1A2 gene; Cardiac; Cardiac Myocytes; Chemosensitization; Chromatin; Clinical; Code; Collagen; Collagen Type I; Data; Elements; 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; Performance; Pharmacotherapy; Phosphorylation; Prevention; Process; Protein Isoforms; Regulator Genes; Research Personnel; Screening procedure; Signal Transduction; Smooth Muscle; Stress; Testing; Therapeutic; Trichostatin A; Ventricular; Ventricular Remodeling; Work; base; chromatin remodeling; clinically relevant; design; efficacy testing; fibrogenesis; in vivo; insight; interstitial; mouse model; novel; novel therapeutic intervention; novel therapeutics; oncology; pressure; programs; research study; response; scriptaid; small molecule; tissue culture

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.

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性调节因子。这些酶起到核整合剂的作用 耦合不同的上游信号来控制基因表达。组蛋白的药理学抑制 脱乙酰酶（HDAC）正在成为肿瘤学领域一种有前景的治疗方法。在这个 根据提案，我们将探索 HDAC 抑制作为心脏病的新疗法。 HDAC 活性的抑制会减弱培养物中心肌细胞的肥大生长。初步的 我们的实验室使用 2 种广谱 HDAC 抑制剂得出的结果表明，可显着抑制肥大 在临床相关的主动脉束带模型中。重要的是，尽管后负荷压力持续存在，HDAC 抑制剂介导的肥厚性生长减弱具有良好的耐受性，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) 似乎会削弱心脏的病理性生长。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，我们建议对压力超负荷肥大和衰竭的动物模型进行研究， 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 抑制剂来确认和扩展我们的初步研究，确定 这些化合物的临床、功能和分子终点，并检查其普遍性 抗肥厚治疗的方法。在目标 2 中，我们将检查我们所选择的分子机制 假设有助于 HDACi 的有益作用，特别是 1) Foxo 活性的增强，以及 2) 抑制 MHC 同工型转换。在目标 3 中，建议进行研究来定义分子机制： 保持收缩性能，包括细胞内 Ca2+ 稳态的变化以及表达和 参与 Ca2+ 处理的蛋白质的磷酸化。在目标 4 中，我们将破译治理机制 HDAC 抑制剂治疗的心脏纤维化减少，测试 HDAC 抑制剂对心脏的影响 培养的心脏成纤维细胞和体内胶原蛋白的生物合成和加工。 这里提出的研究将探讨我们初步观察到的 HDAC 抑制剂的 3 个主要作用 压力应激心肌的研究：肥厚生长减弱，收缩性能保持， 并减少纤维形成。总之，这些研究将提供关于实用性的重要见解。 HDACi 药物疗法作为一种新型抗肥厚策略。