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.

5-Oxo-6,8,11,14-二十碳四烯酸 (5-oxo-ETE) 是一种花生四烯酸代谢物，通过 5-脂氧合酶途径与白三烯一起产生。代谢组学研究表明，急性心肌梗死 (AMI) 患者血清中 5-oxo-ETE 水平升高。 5-oxo-ETE 的作用由高度选择性的氧代二十烷酸受体 (OXE-R) 介导。此外，在 AMI 患者和小鼠中证实了 OXE-R 含量增加。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 5-oxo-ETE 会引发小鼠心肌损伤。通路富集分析确定支链氨基酸转氨酶 1/2 (BCAT1/2) 是这种效应的潜在介质。 Western blot和免疫组织化学分析表明，AMI在体外和体内均显着降低了BCAT1/BCAT2的表达，而药物抑制BCAT1/BCAT2则加速了心肌损伤。相反，小鼠心脏特异性过度表达 BCAT1/BCAT2 可防止缺血性心肌损伤。使用选择性 OXE-R 抑制剂 Gue1654 治疗可通过激活 BCAT1 减轻冠状动脉结扎引起的小鼠缺血性心肌损伤以及缺氧/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。总体而言，我们的研究基于代谢组学证实了治疗 AMI 的新靶点 OXE-R，并且靶向 OXE-R 可能代表着通过激活 BCAT1 对心血管疾病进行未被认识的治疗干预。