BCAA Catabolic Defect in HF: Novel Mechanism and Therapeutic Target

摘要 代谢重塑是心力衰竭发病过程中不可或缺的一部分。从一个不偏不倚的 转录组分析集中在已知的代谢途径上，我们意外地发现了分支链 氨基酸(BCAA)分解代谢途径是小鼠衰竭心脏中受影响最大的途径之一。 随后，我们发现支链氨基酸分解代谢缺陷以及由此导致的心脏内分支- 链酮酸(BCKA)是人体衰竭心脏常见的代谢特征。BCKA的有害影响 心功能的蓄积与其对线粒体ROS诱导和复合体的直接作用有关 I特异性抑制。最重要的是，支链氨基酸分解代谢活性的遗传抑制促进了压力超负荷。 在恢复支链氨基酸分解代谢活性和显著减少BCKA蓄积的同时诱发心力衰竭 使心力衰竭的发作变得迟钝。这些令人兴奋的新发现第一次建立了一个直接的和因果的 支链氨基酸分解代谢缺陷在心力衰竭中的作用，为心力衰竭的治疗提供概念证据 以支链氨基酸分解代谢活动为目标。这些初步数据导致了我们的新假设，即压力诱导 BCAA分解代谢缺陷导致心脏BCKA积聚，对心脏产生不利影响 通过线粒体功能受损和ROS诱导(图1)。在这份提案中，我们将调查 通过积极的体内和体外实验验证我们的假说的正确性，并建立治疗潜力。 为治疗心力衰竭恢复支链氨基酸分解代谢活动。具体地说，我们将完成以下三个具体工作 目的：目的：1.确定心肌细胞支链氨基酸分解代谢缺陷在细胞自主性中的作用。 心力衰竭的发病机制：使用新的小鼠模型，我们将从基因上削弱支链氨基酸分解代谢活性 特别是在成人心肌细胞中，并检测对心功能和病理的直接影响 基础状态下的重构以及对压力超负荷或慢性ISO刺激的响应。目标2.目标 解开BCKA引起心功能障碍的细胞和分子基础：我们将在 体外和体内BCKA蓄积对线粒体功能的特异性影响 复合体I抑制和ROS诱导及BCKA积聚对心肌细胞活力和病理的影响 改建。目的3验证靶向BCKD激酶治疗心力衰竭的可能性。我们会的 检测基因或药物抑制BCKD恢复支链氨基酸分解代谢活性的功能影响 激酶在心力衰竭病理进展中的作用。总而言之，这个项目将揭示一个新颖而重要的方面 心力衰竭的病理重塑，填补了我们目前对心脏的认识上的一个重大空白 并有助于确定这一重大疾病的新治疗靶点。

Abstract Metabolic remodeling is an integral part of pathogenic process of heart failure. From an unbiased transcriptome analysis focusing on known metabolic pathways, we unexpectedly found that branched chain amino acids (BCAA) catabolic pathway is one of the most significantly affected in mouse failure hearts. Subsequently, we revealed that BCAA catabolic defect and the resulted intra-cardiac accumulation of branched- chain keto acid (BCKA) are common metabolic features in human failing hearts. The detrimental impact of BCKA accumulation on cardiac function is associated with its direct effect on mitochondrial ROS induction and complex I specific inhibition. Most importantly, genetic inhibition of BCAA catabolic activity promoted pressure-overload induced heart failure while restoring BCAA catabolic activity and reducing BCKA accumulation significantly blunted the onset of heart failure. These exciting new findings established, for the first time, a direct and causal role of BCAA catabolic defect in heart failure, and provide proof of concept evidence to treat heart failure by targeting BCAA catabolic activity. These preliminary data lead to our novel hypothesis that stress-induced BCAA catabolic defect results in cardiac accumulation of BCKA which exerts detrimental effect on heart via impairment of mitochondria function and ROS induction (Figure 1). In this proposal, we will investigate the validity of our hypothesis via vigorous in vivo and in vitro examination, and establish the therapeutic potential of restoring BCAA catabolic activity for heart failure. Specifically, we will accomplish the following three specific aims: Aim 1. To determine cell-autonomous contribution of BCAA catabolic defect in cardiomyocyte to the pathogenesis of heart failure: Using novel mouse model, we will genetically impair BCAA catabolic activity specifically in adult cardiomyocytes and examine the direct impact on cardiac function and pathological remodeling under basal as well as in response to pressure-overload or chronic ISO stimulation. Aim 2. To unravel the cellular and molecular basis of BCKA induced cardiac dysfunction: We will determine both in vitro and in vivo the specific impact of BCKA accumulation on mitochondrial function, the connection between complex I inhibition and ROS induction, and impact of BCKA accumulation on myocyte viability and pathological remodeling. Aim 3 To validate the therapeutic potential of targeting BCKD Kinase for HF therapy. we will test the function impact of restoring BCAA catabolic activity by genetically or pharmacologically inhibiting BCKD kinase on the pathological progression of HF. Together, this project will uncover a novel and important aspect of pathological remodeling in heart failure, fill a significant gap of knowledge in our current understanding of cardiac pathogenesis, and help to identify novel therapeutic target for this major disease.