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01.12.2021 | Original Contribution

Oxoeicosanoid receptor inhibition alleviates acute myocardial infarction through activation of BCAT1

verfasst von: Qiong Lai, Guangying Yuan, Le Shen, Lu Zhang, Fei Fu, Zeliang Liu, Yuanyuan Zhang, Junping Kou, Shijia Liu, Boyang Yu, Fang Li

Erschienen in: Basic Research in Cardiology | Ausgabe 1/2021

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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.

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Titel: Oxoeicosanoid receptor inhibition alleviates acute myocardial infarction through activation of BCAT1
verfasst von: Qiong Lai
Guangying Yuan
Le Shen
Lu Zhang
Fei Fu
Zeliang Liu
Yuanyuan Zhang
Junping Kou
Shijia Liu
Boyang Yu
Fang Li
Publikationsdatum: 01.12.2021
Verlag: Springer Berlin Heidelberg
Erschienen in: Basic Research in Cardiology / Ausgabe 1/2021
Print ISSN: 0300-8428
Elektronische ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-021-00844-0

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Oxoeicosanoid receptor inhibition alleviates acute myocardial infarction through activation of BCAT1

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