The Branched Chain Ketoacid Dehydrogenase Kinase-Phosphatase System as a New Regulatory Node in Mycocardial Fuel Section

支链酮酸脱氢酶激酶磷酸酶系统作为心肌燃料部分的新调节节点

• 批准号: 10379459
• 负责人: Robert Walker McGarrah
• 金额: $ 14.26万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379459
• 关键词: ATP Citrate (pro-S)-Lyase; Ablation; Affect; Animal Model; Animals; Award; Biochemical; Blood Circulation; Branched-Chain Amino Acids; Cardiac; Cardiometabolic Disease; Catabolism; Citric Acid Cycle; Complex; Coupled; Data; Development; Disease; Drug Targeting; Echocardiography; Enzymes; Fatty Acids; Generations; Genes; Glucose; Glycolysis; Goals; Growth; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hepatic; Impairment; Keto Acids; Knockout Mice; Label; Leucine; Liver; Malonyl Coenzyme A; Measurement; Measures; Mediating; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Molecular; Myocardial; Myocardium; Organ; Oxidoreductase; Palmitates; Pathogenesis; Pathway interactions; Perfusion; Persons; Pharmacology; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physicians; Physiological; Plasma; Process; Production; Protein Dephosphorylation; Reporting; Research; Research Technics; Role; Scientist; Signal Transduction; Structure; Symptoms; System; Techniques; Tissues; Tracer; Wild Type Mouse; amino acid metabolism; base; cardiogenesis; cohort; constriction; coronary fibrosis; experimental study; fatty acid oxidation; fetal; genetic manipulation; glucose metabolism; hemodynamics; improved; inhibitor; insight; lipid metabolism; mTOR Signaling Pathway; mortality; new therapeutic target; novel; oxidation; preference; skills

Despite major treatment advances over the last decades, mortality after the onset of heart failure (HF) symptoms remains extremely high. Changes in cardiac metabolic pathways, a process termed metabolic remodeling, precedes the structural remodeling that occurs with HF progression. During HF, branched-chain amino acids (BCAA) and branched-chain ketoacids (BCKA) increase in circulation. Moreover, the cardiac BCAA metabolic pathway becomes impaired, leading to increased cardiac BCAA and BCKA. The impact of systemic and cardiac-specific BCAA dysregulation on HF pathogenesis is still largely unknown. Using animal models of HF, we have found that HF per se impairs hepatic BCAA metabolism, which may explain the increase in circulating BCAA and BCKA. Additionally, we have found that, in contrast to previous reports, there is negligible entry of cardiac BCAA into the TCA cycle (i.e. anaplerosis). Rather, the heart tends to salvage the BCAA pool through conversion of BCKA into BCAA. Taken together, these findings suggest an unappreciated metabolic interplay between the heart and liver that increases delivery of BCAA and BCKA to the failing heart. Moreover, cardiac BCAA metabolism appears to affect the metabolism of other substrates such as glucose and fatty acids. We recently discovered, in the liver, that the regulatory enzymes that control BCAA metabolism in the mitochondria also regulate a cytosolic enzyme that coordinates glucose and lipid metabolism. It is unknown whether this new metabolic regulatory node has a role in HF. The overall objective of this application is to determine the role of dysregulated systemic and cardiac-specific BCAA metabolism in structural and metabolic remodeling in HF. Our specific aims are (1) To determine how dysregulation of hepatic and cardiac BCAA metabolism during HF contributes to HF pathogenesis and (2) To determine if the regulatory system of cardiac BCAA metabolism also influences fuel preference in the failing heart. To achieve Aim 1, we will generate liver- and heart-specific knockout mice that promote hepatic or cardiac BCAA catabolism, respectively. We will then induce HF in these animals and will characterize the functional and molecular changes in the heart to determine how organ-specific alterations in BCAA metabolism affect HF progression. To achieve Aim 2, we will use state-of-the art metabolic flux techniques in isolated beating hearts from these animals to determine how the genetic manipulations affect cardiac fuel use. If successful, these studies will define new mechanistic bases for structural and metabolic remodeling in the failing heart. Together, these experiments will allow me to build on the following skills: 1) basic biochemical, molecular and metabolic research techniques; 2) generation and utilization of animal models of cardiac disease; and 3) cardiac metabolic and physiological phenotyping. The data gathered during this award period coupled with mentorship from leaders in the fields of basic and translational metabolism research will prepare me to fulfill my long-term goal of becoming an independent physician-scientist in the field of cardiometabolic disease.

尽管在过去几十年中的重大治疗进展，但心力衰竭发作后的死亡率（HF） 症状仍然很高。心脏代谢途径的变化，该过程称为代谢 重塑之前，先于HF进展发生的结构重塑。在HF期间，分支链 氨基酸（BCAA）和分支链酮酸（BCKA）的循环增加。而且，心脏 BCAA代谢途径受到损害，导致心脏BCAA和BCKA增加。的影响 HF发病机理上的全身性和心脏特异性BCAA失调仍然在很大程度上未知。使用动物 HF模型，我们发现HF本身会损害肝BCAA代谢，这可能解释了 循环BCAA和BCKA的增加。此外，我们发现，与以前的报告相比 心脏BCAA可以忽略不计入TCA周期（即无链球菌）。相反，心脏倾向于挽救 BCAA池通过将BCKA转换为BCAA。综上所述，这些发现暗示 心脏和肝脏之间的代谢相互作用会增加BCAA和BCKA的递送到失败的心脏。 此外，心脏BCAA代谢似乎会影响其他底物（例如葡萄糖）的代谢 和脂肪酸。我们最近在肝脏中发现控制BCAA代谢的调节酶 在线粒体中，还调节一种胞质酶，该酶辅助葡萄糖和脂质代谢。这是 未知这种新的代谢调节节点是否在HF中起作用。该应用程序的总体目标 是确定全身和心脏特异性BCAA代谢在结构和 HF中的代谢重塑。我们的具体目的是（1）确定肝和心脏失调的失调 HF期间的BCAA代谢有助于HF发病机理，（2）确定调节系统是否是否 心脏BCAA代谢还影响了衰竭心脏的燃料偏好。为了实现目标1，我们将 产生肝和心脏特异性敲除小鼠，促进肝或心脏BCAA分解代谢， 分别。然后，我们将在这些动物中诱导HF，并表征功能和分子 心脏变化以确定BCAA代谢中器官特异性改变如何影响HF进展。 为了实现目标2，我们将在这些孤立的跳动中使用最先进的代谢通量技术 动物确定遗传操作如何影响心脏燃料的使用。如果成功，这些研究将 定义在失败的心脏中进行结构和代谢重塑的新机械基础。 这些实验将使我能够以以下技能为基础：1）基本的生化，分子和 代谢研究技术； 2）心脏疾病动物模型的产生和利用； 3） 心脏代谢和生理表型。在此奖励期间收集的数据加上 基础和转化代谢研究领域领导者的指导将使我做好准备 在心脏代谢疾病领域成为独立医师科学家的长期目标。

项目成果

Cardiovascular Metabolomics.

• DOI: 10.1161/circresaha.117.311002
• 发表时间: 2018-04-27
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: McGarrah RW;Crown SB;Zhang GF;Shah SH;Newgard CB
• 通讯作者: Newgard CB

Circulating long chain acylcarnitines and outcomes in diabetic heart failure: an HF-ACTION clinical trial substudy.

• DOI: 10.1186/s12933-021-01353-z
• 发表时间: 2021-08-03
• 期刊: Cardiovascular diabetology
• 影响因子: 9.3
• 作者: Truby LK;Regan JA;Giamberardino SN;Ilkayeva O;Bain J;Newgard CB;O'Connor CM;Felker GM;Kraus WE;McGarrah RW;Shah SH
• 通讯作者: Shah SH