Oxoeicosanoid receptor inhibition alleviates acute myocardial infarction through activation of BCAT1

• DOI: 10.1007/s00395-021-00844-0
• Publication Date: 2021-01-23T05:03:24Z
• Authors: Qiong Lai; Guangying Yuan; Le Shen; Lu Zhang; Fei Fu; Zeliang Liu; Yuanyuan Zhang; Junping Kou; Shijia Liu; Boyang Yu; Fang Li
• Keywords: Male; 0303 health sciences; Benzeneacetamides; Myocardial Infarction; NF-kappa B; Apoptosis; Arachidonic Acids; Protein Kinase C-epsilon; Middle Aged; Cell Line; 3. Good health; Enzyme Activation; Mice, Inbred C57BL; Disease Models, Animal; 03 medical and health sciences; Case-Control Studies; Metabolome; Animals; Humans; Female; Myocytes, Cardiac; Benzothiazoles; Aged

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.