Branched Chain Amino Acids and Heart Failure

项目总结 血浆中支链氨基酸(支链氨基酸：亮氨酸、缬氨酸和异亮氨酸)的升高与 并可能先于心力衰竭(HF)的发展。在小鼠中，补充支链氨基酸和 抑制全身支链氨基酸的分解代谢会恶化心脏对挑战的反应。相反，推广 在多种模型中，全身支链氨基酸分解代谢保持心肌收缩能力并减少心室扩张 氢氟酸。因此，支链氨基酸的分解代谢似乎有利于心脏功能。然而，尚不清楚的是， 支链氨基酸的分解代谢需要发生在心脏或其他地方，才能有利于心脏功能。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)BCAA相对于其他底物的分解代谢在失败时比未失败时低 心脏，但正是外周BCAA分解代谢的增加是有益于心脏的关键 功能。为了验证这些假设，我将首先比较支链氨基酸在正常心脏和衰竭心脏中的分解代谢。 然后我将操纵组织特异性支链氨基酸的分解代谢，以确定是否增强了保护作用 支链氨基酸的分解代谢是通过增加支链氨基酸在心脏或其他地方的分解而发生的。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分解代谢是否存在组织特异性变化 失败了。我还将通过量化经心脏途径提取的血浆支链氨基酸，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萃取率会比那些患者低。 没有失败过。在第二部分，我将测试是否促进骨骼肌中支链氨基酸的分解代谢或 仅靠心脏就足以预防心力衰竭。为了做到这一点，我将在BCKDK小鼠中使用组织特异性缺失， 心脏或骨骼肌中支链氨基酸分解代谢限速步骤的关键抑制激酶 并将评估对基础心功能的影响及其对血流动力学和缺血的反应 挑战。我推测，促进骨骼肌而不是心脏中的支链氨基酸分解代谢将 在面临血流动力学和缺血挑战时保护心脏功能。

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.