Autophagy in Metabolic Distress and Cardiac Function: Regulation by the HDAC-FoxO

代谢窘迫和心脏功能中的自噬：HDAC-FoxO 的调节

• 批准号: 9266234
• 负责人: Dian Cao
• 金额: $ 13.21万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266234
• 关键词: Animal Model; Antineoplastic Agents; Autophagocytosis; Biology; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Clinical; Comorbidity; Data; Deacetylation; Development; Diabetes Mellitus; Distress; Elements; Epidemic; FDA approved; FOXO1A gene; FOXO3A gene; Fibrosis; Functional disorder; Genetic Transcription; Gluconeogenesis; Goals; HDAC3 gene; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Hypertension; In Vitro; Lead; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Modeling; Myocardial dysfunction; Myocardium; Obesity; Pathogenesis; Pathologic; Pathway interactions; Patients; Performance; Pharmacology; Positioning Attribute; Prevention; Process; Regulation; Research Personnel; Risk Factors; Role; Scientist; Secondary Myocardial Diseases; Secondary to; Stress; Stress cardiomyopathy; Testing; Therapeutic; Time; Training; Translating; Treatment Failure; Ventricular; Vorinostat; Work; aging population; base; cardiogenesis; cell type; clinically relevant; diabetic cardiomyopathy; in vivo; in vivo Model; insight; interstitial; mitochondrial dysfunction; novel; pressure; prevent; public health relevance; response; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Autophagy in Metabolic Distress and Cardiac Function: Regulation by the HDAC-FoxO Axis Recent work has demonstrated that histone deacetylase [HDAC] inhibition [HDACi] is a promising strategy to target pathological cardiac hypertrophy, a process that can eventually lead to heart failure (HF). We have conducted studies in clinically relevant models of heart disease in vivo, demonstrating that pharmacological suppression of Class I and II HDAC activity inhibits, and even reverses, cardiac hypertrophy in response to pressure overload. At the same time, HDAC inhibition preserves ventricular size and systolic performance and diminishes interstitial fibrosis. In parallel work, we have also identified the transcription factor FoxO3 as a central element in the governance of cardiac catabolic pathways, especially the autophagy-lysosomal process. Furthermore, strong evidence has suggested that Class I and II HDACs (HDAC3, 5, and 9) regulate metabolic processes controlled by FoxO transcription factors (FoxO1 and 3). Moving forward, a leading hypothesis is that HDAC inhibition suppresses maladaptive autophagy and metabolic derangements in pressure overload and metabolic stress induced cardiomyopathy. HDAC inhibitors could target both maladaptive autophagy in hypertension and ameliorate metabolic stresses in diabetes. These agents can potentially turn into powerful ways in preventing and treat heart failure, especially in the current era of epidemic hypertension and diabetes. Also importantly, the HDAC inhibitor vorinostat is a FDA-approved and clinically well tolerated anti-cancer agent. Based on these data, we propose studies to decipher the mechanisms of HDAC-FoxO axis in regulating autophagy and metabolic pathways, a novel mechanism and therapeutic target of cardiomyopathy and HF. HYPOTHESES: HDAC inhibitors suppress cardiomyopathy-promoting maladaptive autophagy and metabolic derangements through regulating the function of FoxO transcription factors. SPECIFIC AIMS: Specific Aim 1. To define the role of HDACs and HDAC inhibition in regulating the function of FoxO transcription factors and autophagy in vitro. Specifi Aim 2. To characterize the role of Class I and II HDACs in regulating cardiomyocyte autophagy and the role(s) of FoxOs therein. Specific Aim 3. To characterize the impact of HDACs (HDAC3, 5 and 9) and HDAC inhibitors on the function of FoxO1 and FoxO3 in models of metabolic stress. Studies proposed here will provide critical insight into how Class I and II HDACs regulate the function of FoxO1 and FoxO3 in the heart; how disturbance of the HDAC-FoxO pathway contributes to maladaptive autophagy, metabolic stress, cardiomyopathy, and pathological cardiac remodeling; how HDAC inhibition suppresses maladaptive autophagy and correct metabolic derangements by inhibiting the function of FoxO transcription factors under a variety of pathological conditions and protects cardiac function. At the same time, this work will move HDAC inhibition forward as a potentially promising therapeutic strategy in heart failure.

描述（由申请人提供）：代谢窘迫和心脏功能中的自噬：HDAC-FoxO 轴的调节最近的工作表明，组蛋白脱乙酰酶 [HDAC] 抑制 [HDACi] 是一种针对病理性心脏肥大的有前景的策略，而病理性心脏肥大是最终导致心力衰竭 (HF) 的过程。我们对临床相关的心脏病体内模型进行了研究，证明药物抑制 I 类和 II 类 HDAC 活性可以抑制甚至逆转压力超负荷引起的心脏肥大。同时，HDAC 抑制可保持心室大小和收缩性能并减少间质纤维化。在并行工作中，我们还确定了转录因子 FoxO3 作为心脏分解代谢途径（尤其是自噬溶酶体过程）调控的核心元件。此外，强有力的证据表明，I 类和 II 类 HDAC（HDAC3、5 和 9）调节由 FoxO 转录因子（FoxO1 和 3）控制的代谢过程。展望未来，一个主要假设是 HDAC 抑制可抑制压力超负荷和代谢应激诱发的心肌病中的适应不良自噬和代谢紊乱。 HDAC 抑制剂可以针对高血压中的适应不良自噬，并改善糖尿病中的代谢应激。这些药物有可能成为预防和治疗心力衰竭的有效方法，特别是在当前高血压和糖尿病流行的时代。同样重要的是，HDAC 抑制剂伏立诺他是 FDA 批准的、临床耐受性良好的抗癌药物。基于这些数据，我们提出研究破译HDAC-FoxO轴调节自噬和代谢途径的机制，这是心肌病和心力衰竭的新机制和治疗靶点。假设：HDAC 抑制剂通过调节 FoxO 转录因子的功能来抑制促进心肌病的适应不良自噬和代谢紊乱。具体目标： 具体目标 1. 明确 HDAC 和 HDAC 抑制在体外调节 FoxO 转录因子和自噬功能中的作用。具体目标 2. 表征 I 类和 II 类 HDAC 在调节心肌细胞自噬中的作用以及 FoxO 在其中的作用。具体目标 3. 表征代谢应激模型中 HDAC（HDAC3、5 和 9）和 HDAC 抑制剂对 FoxO1 和 FoxO3 功能的影响。这里提出的研究将为 I 类和 II 类 HDAC 如何调节心脏中 FoxO1 和 FoxO3 的功能提供重要的见解； HDAC-FoxO 通路的紊乱如何导致适应不良的自噬、代谢应激、心肌病和病理性心脏重塑； HDAC 抑制如何通过在多种病理条件下抑制 FoxO 转录因子的功能来抑制适应不良的自噬并纠正代谢紊乱，并保护心脏功能。同时，这项工作将推动 HDAC 抑制作为心力衰竭的一种潜在有前景的治疗策略。