HDAC Inhibition in Cardiac Hypertrophy and Failure

心脏肥大和衰竭中的 HDAC 抑制

• 批准号: 7339830
• 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/7339830
• 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

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，控制组蛋白乙酰化的酶作为应激- 心脏中基因表达的响应性调节。这些酶作为核整合因子发挥作用 结合不同的上游信号来控制基因表达。组蛋白的药理抑制作用 脱乙酰酶(HDACs)是肿瘤学领域一种很有前途的治疗方法。在这 建议，我们将探索HDAC抑制作为心脏病的一种新疗法。 抑制HDAC活性可抑制培养中心肌细胞的肥大生长。初步 我们实验室使用两种广谱HDAC抑制剂的结果表明，显著抑制了肥厚 在一个临床相关的主动脉环扎模型中。重要的是，尽管持续存在后负荷压力，HDAC 抑制剂介导钝化肥大生长的耐受性良好，心室大小和收缩压 表现得以保留，间质纤维化减轻。因此，HDAC抑制(HDACi) 似乎会阻碍心脏的病理性生长。我们假设用这些(和)抑制HDAC 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。在此，我们提出了压力超负荷性肥厚和衰竭动物模型的研究。 旨在确定HDAC抑制疗法的有效性。在目标1中，我们将研究有限的数量 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，并检验这一点的普适性 抗肥厚治疗的探讨。在目标2中，我们将研究我们选择的分子机制 假设有助于HDACi的有益效果，特别是1)FOXO活性的增强，2) 抑制MHC异构体转换。在目标3中，提出了定义以下分子机制的研究 维持收缩功能，包括细胞内钙稳态的变化及其表达和 参与钙离子处理的蛋白质的磷酸化。在目标4中，我们将破译管理 HDAC抑制剂治疗的心脏纤维化减轻，测试HDAC抑制剂对 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索在我们的初步研究中观察到的HDAC抑制剂的三个主要作用 压力应激心肌的研究：抑制肥大生长，保留收缩功能， 并减少纤维化的发生。综上所述，这些研究将为我们提供有关 HDACi药物治疗作为一种新的抗肥厚策略。