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Oxoeicosanoid receptor inhibition alleviates acute myocardial infarction through activation of BCAT1

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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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Abbreviations

5-oxo-ETE:

5-Oxo-6,8,11,14-eicosatetraenoic acid

OXE-R:

Oxoeicosanoid receptor

AMI:

Acute myocardial infarction

BCAA:

Branched chain amino acid

BCAT1:

Branched-chain-amino-acid aminotransferase, cytosolic

BCAT2:

Branched-chain-amino-acid aminotransferase, mitochondrial

CAL:

Left anterior descending coronary artery ligation

CK:

Creatine kinase

CRP:

C-reactive protein

cTn-I:

Cardiac troponin I

HPLC-Q/TOF–MS:

High-performance liquid chromatography and quadrupole time-of-flight mass spectrometry

LDH:

Lactate dehydrogenase

mTOR:

Mammalian target of rapamycin

NF-κB:

Nuclear factor kappa-B

OPLS-DA:

Orthogonal partial least-squares discriminant analysis

PKC :

Protein kinase c-ε

p-mTOR:

Phosphorylated-mammalian target of rapamycin

PCA:

Principal component analysis

TNF-α:

Tumor necrosis factor-α

VIP:

Variables importance in the projection

FLC:

Ferritin light chain

FHC:

Ferritin heavy chain

GPX4:

Glutathione peroxidase 4

KLF15:

Krüppel-like factor 15

BCKDHA:

Branched-chain keto acid dehydrogenase E1 component α chain

BCKDHB:

Branched chain keto acid dehydrogenase E1, β polypeptide

PFK1:

Phosphofructokinase

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Acknowledgements

We thank Xiaonan Ma (School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University) for help with laser confocal microscopy.

Funding

This research work was supported by the National Natural Science Foundation of China (No. 81774150, No. 81973506, No. 81603328, No. 81573719), Natural Science Foundation of Jiangsu Province (BK20160761), Project funded by China Postdoctoral Science Foundation (2016M600456, 2017T100425), and supported by "Double First-Class" University project (CPU2018GF06, CPU2018GF07), and the Open Projects of the Discipline of Chinese Medicine of Nanjing University of Chinese Medicine supported by the Subject of Academic priority discipline of Jiangsu Higher Education Institutions (NO. ZYX03KF031).

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Correspondence to Shijia Liu, Boyang Yu or Fang Li.

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All animal experiments were performed in accordance to guidelines of the local animal ethics committee.

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Lai, Q., Yuan, G., Shen, L. et al. Oxoeicosanoid receptor inhibition alleviates acute myocardial infarction through activation of BCAT1. Basic Res Cardiol 116, 3 (2021). https://doi.org/10.1007/s00395-021-00844-0

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