Department of Cardiology, Xijing Hospital, Air Force Medical University, Xi'an, China.
Department of Cardiology, Tangdu Hospital, Air Force Medical University, Xi'an, China.
Theranostics. 2020 Apr 27;10(12):5623-5640. doi: 10.7150/thno.44836. eCollection 2020.
: Myocardial vulnerability to ischemia/reperfusion (I/R) injury is strictly regulated by energy substrate metabolism. Branched chain amino acids (BCAA), consisting of valine, leucine and isoleucine, are a group of essential amino acids that are highly oxidized in the heart. Elevated levels of BCAA have been implicated in the development of cardiovascular diseases; however, the role of BCAA in I/R process is not fully understood. The present study aims to determine how BCAA influence myocardial energy substrate metabolism and to further clarify the pathophysiological significance during cardiac I/R injury. : Parameters of glucose and fatty acid metabolism were measured by seahorse metabolic flux analyzer in adult mouse cardiac myocytes with or without BCAA incubation Chronic accumulation of BCAA was induced in mice receiving oral BCAA administration. A genetic mouse model with defective BCAA catabolism was also utilized. Mice were subjected to MI/R and the injury was assessed extensively at the whole-heart, cardiomyocyte, and molecular levels. : We confirmed that chronic accumulation of BCAA enhanced glycolysis and fatty acid oxidation (FAO) but suppressed glucose oxidation in adult mouse ventricular cardiomyocytes. Oral gavage of BCAA enhanced FAO in cardiac tissues, exacerbated lipid peroxidation toxicity and worsened myocardial vulnerability to I/R injury. Etomoxir, a specific inhibitor of FAO, rescued the deleterious effects of BCAA on I/R injury. Mechanistically, valine, leucine and their corresponding branched chain α-keto acid (BCKA) derivatives, but not isoleucine and its BCKA derivative, transcriptionally upregulated peroxisome proliferation-activated receptor alpha (PPAR-α). BCAA/BCKA induced PPAR-α upregulation through the general control nonderepresible-2 (GCN2)/ activating transcription factor-6 (ATF6) pathway. Finally, in a genetic mouse model with BCAA catabolic defects, chronic accumulation of BCAA increased FAO in myocardial tissues and sensitized the heart to I/R injury, which could be reversed by adenovirus-mediated PPAR-α silencing. : We identify BCAA as an important nutrition regulator of myocardial fatty acid metabolism through transcriptional upregulation of PPAR-α. Chronic accumulation of BCAA, caused by either dietary or genetic factors, renders the heart vulnerable to I/R injury via exacerbating lipid peroxidation toxicity. These data support the notion that BCAA lowering methods might be potentially effective cardioprotective strategies, especially among patients with diseases characterized by elevated levels of BCAA, such as obesity and diabetes.
: 心肌对缺血/再灌注（I/R）损伤的易感性严格受能量底物代谢的调控。支链氨基酸（BCAA）由缬氨酸、亮氨酸和异亮氨酸组成，是一组在心脏中高度氧化的必需氨基酸。BCAA 水平升高与心血管疾病的发展有关；然而，BCAA 在 I/R 过程中的作用尚未完全阐明。本研究旨在确定 BCAA 如何影响心肌能量底物代谢，并进一步阐明心脏 I/R 损伤期间的病理生理意义。: 采用 Seahorse 代谢通量分析仪测定成年小鼠心肌细胞中葡萄糖和脂肪酸代谢参数，分别在有无 BCAA 孵育的情况下进行。通过给予口服 BCAA 给药来诱导 BCAA 的慢性积累。还利用了一种缺乏 BCAA 分解代谢的基因小鼠模型。将小鼠进行 MI/R，并在整体心脏、心肌细胞和分子水平上广泛评估损伤情况。: 我们证实，BCAA 的慢性积累增强了成年小鼠心室心肌细胞中的糖酵解和脂肪酸氧化（FAO），但抑制了葡萄糖氧化。口服给予 BCAA 增强了心脏组织中的 FAO，加剧了脂质过氧化毒性，并使心肌对 I/R 损伤更加脆弱。Etomoxir，一种 FAO 的特异性抑制剂，挽救了 BCAA 对 I/R 损伤的有害影响。从机制上讲，缬氨酸、亮氨酸及其相应的支链α-酮酸（BCKA）衍生物，但不是异亮氨酸及其 BCKA 衍生物，转录上调过氧化物酶体增殖物激活受体α（PPAR-α）。BCAA/BCKA 通过一般控制非抑制物-2（GCN2）/激活转录因子-6（ATF6）通路上调 PPAR-α。最后，在一种缺乏 BCAA 分解代谢缺陷的基因小鼠模型中，BCAA 的慢性积累增加了心肌组织中的 FAO，并使心脏对 I/R 损伤敏感，而通过腺病毒介导的 PPAR-α 沉默可以逆转这种情况。: 我们发现 BCAA 是通过转录上调 PPAR-α 来调节心肌脂肪酸代谢的重要营养调节剂。无论是饮食还是遗传因素引起的 BCAA 慢性积累，通过加剧脂质过氧化毒性，使心脏易受 I/R 损伤。这些数据支持这样一种观点，即降低 BCAA 的方法可能是潜在有效的心脏保护策略，特别是在肥胖症和糖尿病等以 BCAA 水平升高为特征的患者中。
