A Metabolomics-Based Study on NMDAR-Mediated Mitochondrial Damage through Calcium Overload and ROS Accumulation in Myocardial Infarction.

BACKGROUND

Coronary artery disease is a leading public health problem. However, the mechanisms underlying mitochondrial damage remain unclear. The present study verified and explored the novel mechanisms underlying ischemic injury based on a metabolomic analysis.

METHODS

Mouse models of acute myocardial infarction were established, and serum samples were collected for targeted liquid chromatography with tandem mass spectrometry analysis. Based on metabolomic analyses, the N-methyl-d-aspartic acid receptor (NMDAR)-related calcium transporting signaling pathway was selected. Primary cardiomyocyte cultures were used, and N-methyl-d-aspartic acid (NMDA) was used as an agonist to confirm the role of NMDAR in ischemic injury. In addition, Bax, Bcl-2, mitochondrial calcium, potential, and mitochondrial reactive oxygen species accumulation were used to explore the role of NMDAR in mitochondrial damage-induced apoptosis.

RESULTS

Glutamate-related metabolism was significantly altered following in acute myocardial infarction. NMDA induces apoptosis under hypoxic conditions NMDAR was translocated to the mitochondrial-related membrane after activation, and its mitochondrial expression was significantly increased (p < 0.05). Mitochondrial damage-induced apoptosis was significantly inhibited by a selective NDMAR antagonist (p < 0.05), while Bax expression was remarkably decreased and Bcl-2 expression was increased (p < 0.05). To further explore the mechanism of NMDAR, mitochondrial calcium, membrane potential, and reactive oxygen species were detected. With NMDAR inhibition under hypoxic conditions, mitochondrial morphology and function were preserved (p < 0.05).

CONCLUSIONS

Our metabolomic study identified NMDAR as a promising target. In conclusion, our study provides solid data for further studies of the role of NMDAR in cardiovascular diseases and a promising target to interfere with apoptosis in acute myocardial infarction.