Oxoeicosanoid receptor inhibition alleviates acute myocardial infarction through activation of BCAT1
Oxoeicosanoid receptor inhibition alleviates acute myocardial infarction through activation of BCAT1
复制标题
氧化二十烷酸受体抑制通过激活 BCAT1 缓解急性心肌梗死
DOI：
10.1007/s00395-021-00844-0
复制
发表时间：
2021-01-01
影响因子：
9.5
通讯作者：
Li, Fang
中科院分区：
文献类型：
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作者：
Lai, Qiong;Yuan, Guangying;Li, Fang
5-氧基-6,8,11,14-二十碳四烯酸（5-氧基- ete）是花生四烯酸与白三烯通过5-脂氧合酶途径产生的代谢物。代谢组学研究表明，急性心肌梗死（AMI）患者血清5-oxo-ETE水平升高。5-oxo-ETE的作用是由高选择性的类氧二十烷受体（OXE-R）介导的。此外，在AMI患者和小鼠中证实了OXE-R含量的增加。然而，OXE-R在AMI中的确切作用尚不清楚。在本研究中，我们证明了5-oxo-ETE可引发小鼠心肌损伤。途径富集分析发现支链氨基酸转氨酶1/2 （BCAT1/2）可能是这一效应的潜在介质。Western blot和免疫组化分析显示，AMI在体外和体内均显著降低BCAT1/BCAT2的表达，而BCAT1/BCAT2的药物抑制加速了心肌损伤。相反，小鼠心脏特异性过表达BCAT1/BCAT2可防止缺血性心肌损伤。选择性OXE-R抑制剂Gue1654通过激活BCAT1减轻小鼠冠状动脉结扎引起的缺血性心肌损伤和氧/葡萄糖剥夺引起的心肌细胞损伤，同时抑制OXE-R抑制的蛋白激酶C-ε (PKC-ε)/核因子κB （NF-κB）信号传导和心肌细胞凋亡。总的来说，我们的研究证实了基于代谢组学治疗AMI的新靶点OXE-R，并且靶向OXE-R可能通过激活BCAT1对心血管疾病进行未被认识的治疗干预。
5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is an arachidonic acid metabolite produced along with leukotrienes via the 5-lipoxygenase pathway. Metabolomics studies have shown that 5-oxo-ETE level is elevated in the serum in acute myocardial infarction (AMI). The actions of 5-oxo-ETE are mediated by the highly selective oxoeicosanoid receptor (OXE-R). Moreover, increased OXE-R content was verified in AMI patients and mice. However, the precise role of OXE-R in AMI is unclear. In the present study, we demonstrate that 5-oxo-ETE triggered myocardial injury in mice. Pathway enrichment analysis identified branched chain amino acid transaminase 1/2 (BCAT1/2) as potential mediators of this effect. Western blot and immunohistochemical analyses showed that BCAT1/BCAT2 expression was significantly reduced by AMI in vitro and in vivo, while pharmacologic inhibition of BCAT1/BCAT2 accelerated myocardial injury. Conversely, heart-specific overexpression of BCAT1/BCAT2 in mice protected against ischemic myocardial injury. Treatment with the selective OXE-R inhibitor Gue1654 alleviated coronary artery ligation-induced ischemic myocardial injury in mice and oxygen/glucose deprivation-induced injury in cardiomyocytes through activation of BCAT1, while inhibiting OXE-R suppressed protein kinase C-ε (PKC-ε)/nuclear factor κB (NF-κB) signaling and cardiomyocyte apoptosis. Overall, our study confirmed a novel target OXE-R for the treatment of AMI based on metabolomics, and targeting OXE-R may represent unrecognized therapeutic intervention for cardiovascular diseases through activation of BCAT1.