Branched Chain Amino Acids and Heart Failure

支链氨基酸与心力衰竭

• 批准号: 9881182
• 负责人: Danielle Murashige
• 金额: $ 3.26万
• 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/9881182
• 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/antagonist; 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.

项目概要 血浆中支链氨基酸（BCAA：亮氨酸、缬氨酸和异亮氨酸）的升高与 伴随或可能先于心力衰竭（HF）的发展。在小鼠中，补充支链氨基酸和 抑制全身 BCAA 分解代谢会恶化心脏对挑战的反应。反之，促进 在多种模型中，全身 BCAA 分解代谢可保持心肌收缩力并减少心室扩张 高频。因此，BCAA 分解代谢似乎有利于心脏功能。然而，不知道的是，是否 支链氨基酸分解代谢需要在心脏或其他地方发生才能有益于心脏功能。事实上，它是 尚不清楚心力衰竭发病过程中心脏支链氨基酸分解代谢是否发生变化。根据我的初步数据，我 假设： 1) 失败时支链氨基酸相对于其他底物的分解代谢低于未失败时的分解代谢 心脏，但 2) 外周 BCAA 分解代谢的增加对于心脏有益至关重要 功能。为了检验这些假设，我将首先比较正常心脏和衰竭心脏中支链氨基酸的分解代谢。 然后我将操纵组织特异性 BCAA 分解代谢，以确定是否增强了保护作用 BCAA 分解代谢是通过增加心脏或其他部位的 BCAA 分解而发生的。在我的第一个目标中，我会 确定小鼠心脏模型中支链氨基酸的分解代谢是否存在组织特异性变化 失败。我还将通过量化血浆 BCAA 的经心脏提取，将这些研究扩展到人类。 我假设心力衰竭患者的心脏 BCAA 提取率低于那些患者 没有失败。在第二部分中，我将测试是否促进骨骼肌或骨骼肌中的 BCAA 分解代谢。 仅心脏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 分解代谢限速步骤的关键抑制性激酶 并将评估对基线心脏功能及其对血流动力学和缺血反应的影响 挑战。我假设促进骨骼肌中的 BCAA 分解代谢，而不是心脏中的分解代谢，将 面对血流动力学和缺血挑战时保护心脏功能。