Oxoeicosanoid receptor inhibition alleviates acute myocardial infarction through activation of BCAT1.
Basic Res Cardiol
; 116(1): 3, 2021 01 23.
Article
en En
| MEDLINE
| ID: mdl-33484341
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ácidos Araquidónicos
/
Receptores Eicosanoides
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Miocitos Cardíacos
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Bencenoacetamidas
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Benzotiazoles
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Transaminasas
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Infarto del Miocardio
Tipo de estudio:
Observational_studies
/
Prognostic_studies
Límite:
Aged
/
Animals
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Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Basic Res Cardiol
Año:
2021
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Alemania