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

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

Acute Effects of Cinnamon Spice on Post-prandial Glucose and Insulin in Normal Weight and Overweight/Obese Subjects: A Pilot Study.

肉桂香料对正常体重和超重/肥胖受试者的后葡萄糖和胰岛素的急性影响：一项初步研究。

• DOI: 10.3389/fnut.2020.619782
• 发表时间: 2020
• 期刊: Frontiers in nutrition
• 影响因子: 5
• 作者: Wang J;Wang S;Yang J;Henning SM;Ezzat-Zadeh Z;Woo SL;Qin T;Pan Y;Tseng CH;Heber D;Li Z
• 通讯作者: Li Z