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: 8843944
• 负责人: Dian Cao
• 金额: $ 13.23万
• 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/8843944
• 关键词: Animal Model; Antineoplastic Agents; Autophagocytosis; Biology; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Clinical; Comorbidity; Data; Deacetylation; Development; Diabetes Mellitus; Distress; Epidemic; FDA approved; Fibrosis; Functional disorder; Gluconeogenesis; Goals; HDAC3 gene; Health; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; Human; Hypertension; In Vitro; Indium; Lead; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Modeling; Myocardial dysfunction; Myocardium; Obesity; Pathogenesis; Pathway interactions; Patients; Performance; Positioning Attribute; Prevention; Process; Regulation; Research Personnel; Risk Factors; Role; Scientist; Secondary to; Staging; Stress; Testing; Therapeutic; Time; Training; Translating; Ventricular; Vorinostat; Work; aging population; base; cell type; clinically relevant; diabetic cardiomyopathy; in vivo; in vivo Model; insight; interstitial; mitochondrial dysfunction; novel; pressure; prevent; 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轴的调节最近的研究表明，组蛋白脱乙酰酶[HDAC]抑制[HDACi]是靶向病理性心脏肥大的有希望的策略，病理性心脏肥大是最终导致心力衰竭（HF）的过程。我们已经在体内心脏病的临床相关模型中进行了研究，证明了I类和II类HDAC活性的药理学抑制抑制，甚至逆转了响应于压力超负荷的心脏肥大。与此同时，HDAC抑制可以保留心室大小和收缩性能，并减少间质纤维化。在平行的工作中，我们还确定了转录因子FoxO 3作为心脏分解代谢途径，特别是自噬-溶酶体过程的治理的核心要素。此外，强有力的证据表明，I类和II类HDAC（HDAC 3，5和9）调节由FoxO转录因子（FoxO 1和3）控制的代谢过程。展望未来，一个主要的假设是HDAC抑制抑制压力超负荷和代谢应激诱导的心肌病中的适应不良自噬和代谢紊乱。HDAC抑制剂可以靶向高血压中的适应不良自噬和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，特别是在当前流行性高血压和糖尿病的时代。同样重要的是，HDAC抑制剂vorinostat是FDA批准的临床耐受性良好的抗癌药物。基于这些数据，我们提出了研究来破译HDAC-FoxO轴在调节自噬和代谢途径中的机制，这是心肌病和HF的新机制和治疗靶点。假设：HDAC抑制剂通过调节FoxO转录因子的功能抑制心肌病促进的适应不良自噬和代谢紊乱。具体目标：具体目标1。探讨HDAC及其抑制剂在FoxO转录因子功能和自噬中的作用。第二章.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HDAC（HDAC 3、5和9）和HDAC抑制剂对代谢应激模型中FoxO 1和FoxO 3功能的影响。本文提出的研究将提供关键的洞察I类和II类HDAC如何调节心脏中FoxO 1和FoxO 3的功能; HDAC-FoxO通路的干扰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抑制如何通过抑制FoxO转录因子的功能来抑制适应不良的自噬和纠正代谢紊乱，调节和保护心脏功能。同时，这项工作将推动HDAC抑制作为心力衰竭的潜在有前途的治疗策略。