Branched Chain Amino Acids and Heart Failure

支链氨基酸与心力衰竭

• 批准号: 10337183
• 负责人: Danielle Murashige
• 金额: $ 3.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337183
• 关键词: Ablation; Adult; Affect; Animals; Blood; Branched-Chain Amino Acids; Cardiac; Cardiotoxicity; Cardiovascular Diseases; Catabolism; Chronic; Citric Acid Cycle; Coronary Arteriosclerosis; Data; Development; Diet; Dietary Supplementation; Echocardiography; Environment; Enzymes; Failure; Functional disorder; Goals; Health Expenditures; Heart; Heart Diseases; Heart failure; Human; Infarction; Infusion procedures; Isoleucine; Knock-out; Label; Leucine; Metabolic; Modeling; Morbidity - disease rate; Mus; Muscle; Myocardial Infarction; Myocardial Ischemia; Myocardium; Pathogenesis; Patients; Pennsylvania; Peripheral; Phosphoric Monoester Hydrolases; Phosphotransferases; Physicians; Physiology; Plasma; Public Health; Reperfusion Injury; Running; Sampling; Scientist; Serum; Skeletal Muscle; Supplementation; Testing; Tissues; Transcript; Translating; Universities; Valine; Ventricular; Ventricular Fibrillation; Work; amino acid metabolism; base; cardiogenesis; cardioprotection; cardiovascular disorder therapy; constriction; design; experimental study; falls; heart function; heart metabolism; heart preservation; hemodynamics; human subject; improved; in vivo; inhibitor; ischemic injury; liquid chromatography mass spectrometry; mortality; mouse model; pressure; prevent; protective effect; response; small molecule; targeted treatment

PROJECT SUMMARY Elevations of branched chain amino acids (BCAAs: leucine, valine, and isoleucine) in plasma are associated with, and may precede, the development of heart failure (HF). In mice, both supplementation of BCAAs and inhibition of whole-body BCAA catabolism worsen cardiac response to challenge. Conversely, promoting whole-body BCAA catabolism preserves cardiac contractility and reduces ventricular dilation in multiple models of HF. BCAA catabolism thus appears to benefit cardiac function. What is not known, however, is whether BCAA catabolism needs to occur in the heart or elsewhere in order to benefit cardiac function. In fact, it is unknown whether cardiac BCAA catabolism changes during HF pathogenesis. Based on my preliminary data, I hypothesize that: 1) the catabolism of BCAAs relative to other substrates is lower in failing than in non-failing hearts, but 2) it is the increase in peripheral BCAA catabolism that is critically needed to benefit cardiac function. To test these hypotheses, I will first compare the catabolism of BCAAs in the normal and failing heart. I will then manipulate tissue-specific BCAA catabolism to determine whether the protective effect of enhanced BCAA catabolism occurs by increasing BCAA breakdown in the heart or elsewhere. In my first aim, I will determine whether there are tissue-specific changes in the catabolism of BCAAs in murine models of heart failure. I will also extend these studies to humans by quantifying the transcardiac extraction of plasma BCAAs. I hypothesize that patients with heart failure will have a lower cardiac BCAA extraction ratio than those patients without failure. In the second part, I will test whether promoting BCAA catabolism in the skeletal muscle or the heart alone is sufficient to prevent heart failure. To do this, I will use tissue-specific deletion in mice of BCKDK, a key inhibitory kinase of the rate-limiting step of BCAA catabolism, in either the heart or the skeletal muscle and will assess the effects on baseline cardiac function and on its response to hemodynamic and ischemic challenges. I hypothesize that promoting BCAA catabolism in the skeletal muscle, but not in the heart, will protect cardiac function in the face of hemodynamic and ischemic challenges.

项目摘要 血浆中支链氨基酸（BCAA：亮氨酸、缬氨酸和异亮氨酸）的升高与 与心力衰竭（HF）的发展同时发生，并且可能先于心力衰竭（HF）的发展。在小鼠中，补充支链氨基酸和 全身BCAA催化剂抑制使心脏对激发的反应恶化。相反，促进 在多种模型中，全身BCAA catalysts保留心肌收缩力并减少心室扩张 的HF。因此，BCAA catastrophe似乎有益于心脏功能。然而，目前尚不清楚的是， BCAA催化剂需要发生在心脏或其他地方，以有利于心脏功能。其实是 尚不清楚心脏BCAA catalysts是否在HF发病过程中发生变化。根据初步数据，我 假设：1）BCAA相对于其他底物的催化活性在失效中低于非失效中 心脏，但2）这是增加外周BCAA catalogues是至关重要的，以有利于心脏 功能为了验证这些假设，我将首先比较正常和衰竭心脏中BCAA的浓度。 然后，我将操纵组织特异性BCAA catalysts，以确定是否增强的保护作用， BCAA catastrophic发生增加BCAA分解在心脏或其他地方。在我的第一个目标，我将 确定在小鼠心脏模型中BCAA的催化活性是否存在组织特异性变化 失败我还将通过量化血浆支链氨基酸的经心提取来将这些研究扩展到人类。 我假设心力衰竭患者的心脏支链氨基酸提取率比那些 没有失败。在第二部分中，我将测试是否促进BCAA在骨骼肌或 心脏本身就足以预防心力衰竭。为此，我将在BCKDK小鼠中使用组织特异性缺失， 心脏或骨骼肌中BCAA催化剂限速步骤的关键抑制性激酶 并将评估对基线心功能的影响及其对血流动力学和缺血性反应的影响。 挑战我推测，促进骨骼肌中的BCAA catalysts，而不是在心脏中， 在面临血流动力学和缺血性挑战时保护心脏功能。