1. Academic Validation
  2. Oxoeicosanoid receptor inhibition alleviates acute myocardial infarction through activation of BCAT1

Oxoeicosanoid receptor inhibition alleviates acute myocardial infarction through activation of BCAT1

  • Basic Res Cardiol. 2021 Jan 23;116(1):3. doi: 10.1007/s00395-021-00844-0.
Qiong Lai 1 Guangying Yuan 1 Le Shen 2 Lu Zhang 1 Fei Fu 1 Zeliang Liu 1 Yuanyuan Zhang 1 Junping Kou 1 Shijia Liu 3 Boyang Yu 4 Fang Li 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China.
  • 2 Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China.
  • 3 Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China. liushijia2011@163.com.
  • 4 Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China. boyangyu59@163.com.
  • 5 Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China. lifangcpu@163.com.
Abstract

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.

Keywords

5-oxo-6,8,11,14-eicosatetraenoic acid; Acute myocardial infarction; BCAT1/BCAT2; Cardiovascular disease; Metabolomics; OXE receptor.

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