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

项目总结/摘要 自噬在代谢性应激和心功能中的作用：HDAC-FoxO轴的调节 最近的研究表明，组蛋白去乙酰化酶[HDAC]抑制[HDACi]是一种有前途的策略， 靶向病理性心脏肥大，这是一个最终可能导致心力衰竭（HF）的过程。我们有 在体内心脏病的临床相关模型中进行了研究，证明药理学 抑制I类和II类HDAC活性可抑制甚至逆转响应于 压力过载同时，HDAC抑制保留了心室大小和收缩性能， 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作为一个转录因子。 在心脏分解代谢途径，特别是自噬-溶酶体过程的管理中心元素。 此外，强有力的证据表明I类和II类HDAC（HDAC 3、5和9）调节代谢 由FoxO转录因子（FoxO 1和3）控制的过程。向前看，一个主要的假设是， HDAC抑制可抑制压力超负荷中的适应不良自噬和代谢紊乱， 代谢应激诱发心肌病。HDAC抑制剂可以靶向适应不良的自噬， 高血压和改善糖尿病中代谢应激。这些代理人可能会变成强大的 特别是在高血压和糖尿病流行的当今时代， 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， 剂基于这些数据，我们提出了研究，以破译HDAC-FoxO轴在调节 自噬和代谢途径，心肌病和HF的新机制和治疗靶点。 假设：HDAC抑制剂抑制心肌病促进的适应不良自噬， 通过调节FoxO转录因子的功能来调节代谢紊乱。 具体目标：具体目标1。为了明确HDAC和HDAC抑制在调节功能中的作用， FoxO转录因子和自噬的体外研究。具体目标2。描述I类和II类的作用 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。到 表征HDAC（HDAC 3、5和9）和HDAC抑制剂对FoxO 1和FoxO 3功能的影响 在代谢应激模型中。这里提出的研究将提供关键的洞察I类和II类HDAC如何 调节FoxO 1和FoxO 3在心脏中的功能; 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抑制如何抑制适应不良的自噬和纠正代谢紊乱， 在各种病理条件下，FoxO转录因子的功能和保护心脏功能。 同时，这项工作将推动HDAC抑制作为一种潜在的有前途的治疗策略， 心衰

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.