BCAA Catabolic Defect in HF: Novel Mechanism and Therapeutic Target

心力衰竭中的 BCAA 分解代谢缺陷：新机制和治疗靶点

• 批准号: 10063896
• 负责人: Zhaoping Li
• 金额: $ 39万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-18 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063896
• 关键词: Adult; Advanced Development; Affect; Amino Acids; Area; Branched-Chain Amino Acids; Carbohydrates; Cardiac; Cardiac Myocytes; Cardiomyopathies; Catabolism; Cells; Chronic; Complex; DNA Sequence Alteration; Data; Defect; Disease; Disease Progression; Essential Amino Acids; Fatty Acids; Genes; Genetic; Glycolysis; Heart; Heart Diseases; Heart failure; Human; Impairment; In Vitro; Isoleucine; Keto Acids; Knock-out; Knowledge; Lead; Leucine; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Mitochondria; Molecular; Mus; Muscle Cells; Myocardial dysfunction; Outcome; Oxidoreductase; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Pharmacology; Phenotype; Phosphotransferases; Prevention Protocols; Process; Production; Publishing; Respiration; Role; Stress; Testing; Therapeutic; Therapeutic Effect; Time; Translational Research; Treatment Efficacy; Valine; amino acid metabolism; amino group; autism spectrum disorder; base; conditional knockout; editorial; heart function; human disease; in vivo; inhibitor/antagonist; kinase inhibitor; mouse model; new therapeutic target; novel; pressure; response; targeted treatment; therapeutic target; transcriptome; translational medicine

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.

摘要 代谢重构是心力衰竭发病过程的重要组成部分。从未偏置 转录组分析集中在已知的代谢途径，我们意外地发现， 氨基酸（BCAA）分解代谢途径是小鼠心力衰竭中最受影响的途径之一。 随后，我们揭示了支链氨基酸分解代谢缺陷和由此导致的心脏内积累的分支- 链酮酸（BCKA）是人类衰竭心脏的常见代谢特征。BCKA的负面影响 累积对心脏功能的影响与其对线粒体ROS诱导和复合物的直接作用有关。 I特异性抑制。最重要的是，BCAA分解代谢活性的遗传抑制促进了压力超负荷 诱导心力衰竭，同时恢复BCAA分解代谢活性并显著减少BCKA积累 减缓了心力衰竭的发作这些令人兴奋的新发现首次建立了一个直接的因果关系， BCAA分解代谢缺陷在心力衰竭中的作用，并提供通过以下方法治疗心力衰竭的概念证据 针对支链氨基酸分解代谢活性。这些初步数据导致我们的新假设，即压力诱导的 BCAA分解代谢缺陷导致BCKA在心脏蓄积，对心脏产生不利影响 通过损害线粒体功能和ROS诱导（图1）。在这份提案中，我们将调查 通过强有力的体内和体外检查验证我们假设的有效性，并确定治疗潜力 恢复支链氨基酸分解代谢活性的方法具体来说，我们将做好以下三个具体工作 目标：目标1。为了确定心肌细胞中BCAA分解代谢缺陷的细胞自主贡献， 心力衰竭的发病机制：使用新的小鼠模型，我们将遗传损害BCAA分解代谢活性 特别是在成年心肌细胞中，并检查对心脏功能和病理学的直接影响。 在基础下以及响应于压力超负荷或慢性ISO刺激的重构。目标2.到 解开BCKA诱导心功能不全的细胞和分子基础：我们将确定这两个在 体外和体内BCKA积累对线粒体功能的具体影响， 复合物I抑制和ROS诱导，以及BCKA积累对肌细胞活力和病理 重塑目的3验证以BCKD激酶为靶点治疗心衰的可能性。我们将 测试通过遗传或非遗传抑制BCKD恢复BCAA分解代谢活性的功能影响 激酶对HF病理进展的影响。总之，这个项目将揭示一个新的和重要的方面， 心力衰竭中的病理性重构，填补了我们目前对心脏病的认识中的一个重大空白。 发病机制，并帮助确定这种主要疾病的新的治疗靶点。

项目成果

Low-Dose Sorafenib Acts as a Mitochondrial Uncoupler and Ameliorates Nonalcoholic Steatohepatitis.

低剂量索拉非尼作为线粒体解偶联剂并改善非酒精性脂肪性肝炎

• DOI: 10.1016/j.cmet.2020.04.011
• 发表时间: 2020-05-05
• 期刊: CELL METABOLISM
• 影响因子: 29
• 作者: Jian, Chongshu;Fu, Jiajun;Cheng, Xu;Shen, Li-Jun;Ji, Yan-Xiao;Wang, Xiaoming;Pan, Shan;Tian, Han;Tian, Song;Liao, Rufang;Song, Kehan;Wang, Hai-Ping;Zhang, Xin;Wang, Yibin;Huang, Zan;She, Zhi-Gang;Zhang, Xiao-Jing;Zhu, Lihua;Li, Hongliang
• 通讯作者: Li, Hongliang

Branched-Chain Amino Acid Negatively Regulates KLF15 Expression via PI3K-AKT Pathway.

支链氨基酸通过 PI3K-AKT 途径负调节 KLF15 表达

• DOI: 10.3389/fphys.2017.00853
• 发表时间: 2017
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Liu Y;Dong W;Shao J;Wang Y;Zhou M;Sun H
• 通讯作者: Sun H

A new branch connecting thermogenesis and diabetes.

• DOI: 10.1038/s42255-019-0112-1
• 发表时间: 2019-09
• 期刊: NATURE METABOLISM
• 影响因子: 20.8
• 作者: Sun, Haipeng;Wang, Yibin
• 通讯作者: Wang, Yibin

Metal dependent protein phosphatase PPM family in cardiac health and diseases.

• DOI: 10.1016/j.cellsig.2021.110061
• 发表时间: 2021-09
• 期刊: CELLULAR SIGNALLING
• 影响因子: 4.8
• 作者: Gao, Chen;Cao, Nancy;Wang, Yibin
• 通讯作者: Wang, Yibin

Effects of branched-chain amino acids on glucose metabolism in obese, prediabetic men and women: a randomized, crossover study.

• DOI: 10.1093/ajcn/nqz024
• 发表时间: 2019-06
• 期刊: The American journal of clinical nutrition
• 作者: S. Woo;Jieping Yang;Mark Hsu;Alicia Yang;Lijun Zhang;Ru-po Lee;Irene Gilbuena;G. Thames;Jianjun Huang;Anna Rasmussen;C. Carpenter;S. Henning;D. Heber;Yibin Wang;Zhaoping Li