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

描述（由申请人提供）：代谢窘迫和心功能中的自噬：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）是一种很有前途的策略，可以靶向病理性心脏肥大，这一过程最终会导致心力衰竭（HF）。我们在心脏疾病的体内临床相关模型中进行了研究，证明药物抑制I类和II类HDAC活性可以抑制甚至逆转压力过载时的心脏肥厚。同时，抑制HDAC可保持心室大小和收缩性能，减少间质纤维化。在平行工作中，我们还发现转录因子FoxO3是控制心脏分解代谢途径，特别是自噬溶酶体过程的核心因素。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（fox01和3）控制的代谢过程。展望未来，一个主要的假设是HDAC抑制抑制压力过载和代谢应激引起的心肌病的不适应自噬和代谢紊乱。HDAC抑制剂可以针对高血压患者的不适应自噬和改善糖尿病患者的代谢应激。这些药物可能会成为预防和治疗心力衰竭的有效方法，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HDAC-FoxO轴调控自噬和代谢途径的机制，这是心肌病和心衰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促进心肌病的不适应自噬和代谢紊乱。明确的目标：明确的目标明确HDAC及抑制HDAC在体外调节FoxO转录因子功能和自噬中的作用。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FoxOs在其中的作用。具体目标3。表征HDAC （HDAC3、5和9）和HDAC抑制剂对代谢应激模型中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的功能提供关键见解；HDAC-FoxO通路的紊乱如何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抑制如何在多种病理条件下通过抑制FoxO转录因子的功能抑制适应性不良的自噬，纠正代谢紊乱，保护心功能。同时，这项工作将推动HDAC抑制作为一种潜在的有前途的心力衰竭治疗策略向前发展。

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.