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.

抽象的 代谢重塑是心力衰竭致病过程不可或缺的一部分。来自公正的 转录组分析以已知的代谢途径为重点，我们出乎意料地发现了分支链 氨基酸（BCAA）分解代谢途径是小鼠衰竭心脏中最显着影响的途径之一。 随后，我们揭示了BCAA的分解代谢缺陷以及分支 - 分支内部的积累 链酮酸（BCKA）是人类失败心脏中常见的代谢特征。 BCKA的不利影响 心脏功能上的积累与其直接影响线粒体ROS诱导和复合物有关 我具体的抑制作用。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 诱发心力衰竭，同时恢复BCAA分解代谢活性并大大减少BCKA积累 心力衰竭发作。这些令人兴奋的新发现首次建立了直接和因果关系 BCAA分解代谢缺陷在心力衰竭中的作用，并提供概念证据证据以治疗心力衰竭 靶向BCAA分解代谢活性。这些初步数据导致了我们的新假设，即应力诱导 BCAA分解代谢缺陷导致BCKA的心脏积累，对心脏施加不利影响 通过损害线粒体功能和ROS诱导（图1）。在此提案中，我们将调查 我们假设通过体内和体外检查的有效性，并建立治疗潜力 恢复心力衰竭的BCAA分解代谢活性。具体来说，我们将完成以下三个特定的 目的：目的1。确定心肌细胞中BCAA分解代谢缺陷的细胞自主贡献 心力衰竭的发病机理：使用新型小鼠模型，我们将遗传损害BCAA分解代谢活性 特别是成人心肌细胞，并检查对心脏功能和病理的直接影响 在基础和响应压力越过或慢性ISO刺激下进行重塑。目标2 揭示BCKA诱导心脏功能障碍的细胞和分子基础：我们将确定两者在 体外和体内BCKA积累对线粒体功能的具体影响， 复杂的I抑制和ROS诱导，以及BCKA积累对肌细胞生存能力和病理的影响 重塑。目标3以验证靶向HF治疗的BCKD激酶的治疗潜力。我们将 测试通过遗传或药理抑制BCKD恢复BCAA分解代谢活性的功能 HF病理进展的激酶。该项目一起将发现一个新颖而重要的方面 心力衰竭的病理重塑，在我们当前对心脏的理解中填补了很大的知识空白 发病机理，有助于确定这种主要疾病的新型治疗靶标。

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

The right ventricular transcriptome signature in Ossabaw swine with cardiometabolic heart failure: implications for the coronary vasculature.

患有心脏代谢性心力衰竭的奥萨博猪的右心室转录组特征：对冠状动脉血管系统的影响。

• DOI: 10.1152/physiolgenomics.00093.2020
• 发表时间: 2021
• 期刊: Physiological genomics
• 影响因子: 4.6
• 作者: Kelly,ShannonC;Rau,ChristophD;Ouyang,An;Thorne,PamelaK;Olver,TDylan;Edwards,JennaC;Domeier,TimothyL;Padilla,Jaume;Grisanti,LaurelA;Fleenor,BradleyS;Wang,Yibin;Rector,RScott;Emter,CraigA
• 通讯作者: Emter,CraigA