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

项目摘要/摘要 代谢性窘迫和心功能中的自噬：HDAC-FoxO轴的调节 最近的工作表明，组蛋白脱乙酰酶[HDAC]抑制[HDACi]是一种很有前途的策略 靶向病理性心肌肥大，这一过程最终可能导致心力衰竭(HF)。我们有 在体内进行了临床相关的心脏病模型的研究，证明了药理学 抑制I和II类HDAC活性可抑制甚至逆转心肌肥厚 压力过载。同时，抑制HDAC可保留心室大小和收缩功能，并 减少间质纤维化。在平行工作中，我们还鉴定了转录因子FOX03是一种 心脏分解代谢途径，特别是自噬-溶酶体过程的控制中心要素。 此外，强有力的证据表明，I类和II类HDAC(HDAC3、5和9)调节新陈代谢 由FoxO转录因子(FoxO1和Fox3)控制的过程。展望未来，一个主要的假设是 HDAC抑制抑制压力超负荷和高血压患者的不适应性自噬和代谢紊乱 代谢应激引起的心肌病。HDAC抑制剂可以靶向两种不良适应自噬 高血压和改善糖尿病的代谢压力。这些代理可能会变成强大的 预防和治疗心力衰竭的方法，特别是在当前流行高血压和糖尿病的时代。 同样重要的是，hdac抑制剂voinostat是fda批准的、临床耐受性良好的抗癌药物。 探员。基于这些数据，我们提出了破译HDAC-FoxO轴调节机制的研究 自噬和代谢途径，心肌病和心力衰竭的新机制和治疗靶点。 假设：HDAC抑制剂抑制促进心肌病适应不良的自噬和 通过调节FoxO转录因子的功能引起代谢紊乱。 特定目标：特定目标1.明确HDAC和HDAC抑制在调节功能中的作用 FoxO转录因子和体外自噬。具体目标2.确定第一类和第二类的作用 HDAC在调节心肌细胞自噬中的作用及FOX在其中的作用(S)。具体目标3.至 描述HDACs(HDAC3、5和9)和HDAC抑制剂对FOXO1和FOX03功能的影响 在新陈代谢应激模型中。这里提出的研究将提供对I类和II类HDAC如何 调节心脏中FoxO1和FoxO_3的功能；HDAC-FoxO通路的紊乱 导致适应性不良的自噬、代谢应激、心肌病和病理性心脏重构； HDAC抑制如何抑制适应性不良的自噬和纠正代谢紊乱 FoxO转录因子在各种病理条件下的作用，保护心脏功能。 与此同时，这项工作将推动HDAC抑制作为一种潜在的有希望的治疗策略在 心力衰竭。

PROJECT SUMMARY/ABSTRACT 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. Specific 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.