Branched chain amino acids exacerbate myocardial ischemia/reperfusion vulnerability via enhancing GCN2/ATF6/PPAR-α pathway-dependent fatty acid oxidation
Branched chain amino acids exacerbate myocardial ischemia/reperfusion vulnerability via enhancing GCN2/ATF6/PPAR-α pathway-dependent fatty acid oxidation
复制标题
支链氨基酸通过增强 GCN2/ATF6/PPAR-α 通路依赖性脂肪酸氧化而加剧心肌缺血/再灌注脆弱性
DOI：
10.7150/thno.44836
复制
发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Tao, Ling
中科院分区：
文献类型：
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作者：
Li, Yueyang;Xiong, Zhenyu;Tao, Ling
原理：心肌对缺血/再灌注(I/R)损伤的易感性受到能量底物代谢的严格调控。支链氨基酸(BCAA)由缬氨酸、亮氨酸和异亮氨酸组成，是一类在心脏中高度氧化的必需氨基酸。支链氨基酸水平升高与心血管疾病的发生有关，但支链氨基酸在I/R过程中的作用尚不完全清楚。本研究旨在探讨支链氨基酸对心肌能量底物代谢的影响，进一步阐明支链氨基酸在心脏I/R损伤中的病理生理学意义。方法：用海马代谢流量分析仪测定BCAA孵育前后成年小鼠心肌细胞的葡萄糖和脂肪酸代谢参数。口服支链氨基酸可诱导小鼠体内支链氨基酸的慢性蓄积。还利用了支链氨基酸分解代谢缺陷的遗传性小鼠模型。小鼠接受MI/R，在全心、心肌细胞和分子水平上对损伤进行了广泛的评估。结果：我们证实，BCAA的慢性积累促进了成年小鼠心肌细胞的糖酵解和脂肪酸氧化，但抑制了葡萄糖的氧化。口服支链氨基酸可增加心肌组织中粮农组织的含量，加重脂质过氧化毒性，加重心肌对I/R损伤的易感性。FAO的特异性抑制剂依托托莫昔尔可拮抗支链氨基酸对I/R损伤的毒害作用。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，而不是异亮氨酸及其BCKA衍生物，转录上调的是过氧化体增殖激活受体α(PPAR-α)。BCAA/BCKA通过一般控制的不可逆转录因子-2(GCN2)/激活转录因子-6(ATF6)途径诱导PPAR-α上调。最后，在支链氨基酸分解代谢缺陷的遗传小鼠模型中，支链氨基酸的长期积累增加了心肌组织中的粮农组织，并使心脏对I/R损伤敏感，这可以通过腺病毒介导的PPAR-α沉默来逆转。结论：通过PPAR-α的转录上调，我们确定支链氨基酸是心肌脂肪酸代谢的重要营养调节因子。由饮食或遗传因素引起的支链氨基酸的慢性积聚，通过加剧脂质过氧化毒性，使心脏容易受到I/R损伤。这些数据支持这样一种观点，即降低支链氨基酸水平的方法可能是潜在有效的心脏保护策略，特别是在以支链氨基酸水平升高为特征的疾病患者中，如肥胖和糖尿病。
Rationale: 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. Methods: 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. Results: 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. Conclusions: 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.