Kaohsiung Journal of Medical Sciences (Nov 2022)

MiR‐199a‐5p promotes ferroptosis‐induced cardiomyocyte death responding to oxygen–glucose deprivation/reperfusion injury via inhibiting Akt/eNOS signaling pathway

  • Guo‐Yong Zhang,
  • Ying Gao,
  • Xin‐Ying Guo,
  • Guo‐Hong Wang,
  • Cai‐Xia Guo

DOI
https://doi.org/10.1002/kjm2.12605
Journal volume & issue
Vol. 38, no. 11
pp. 1093 – 1102

Abstract

Read online

Abstract Myocardial ischemia/reperfusion (I/R) injury is associated with the poor outcome and higher mortality after myocardial infarction. Recent studies have revealed that miR‐199a‐5p participates in the process of myocardial I/R injury, but the precise roles and molecular mechanisms of miR‐199a‐5p in myocardial I/R injury remain not well‐studied. Ferroptosis has been proposed to promote cardiomyocyte death, closely associated with myocardial I/R injury. Herein, the present study aimed to explore the function and mechanisms by which miR‐199a‐5p regulates whether miR‐199a‐5p contributes to ferroptosis‐induced cardiomyocyte death responding to oxygen–glucose deprivation/reoxygenation (OGD/R) injury, an in vitro model of myocardial I/R injury focusing on Akt/eNOS signaling pathway. The results found that ferroptosis‐induced cardiomyocyte death occurs and is accompanied by an increase in miR‐199a‐5p level in OGD/R‐treated H9c2 cells. MiR‐199a‐5p inhibitor ameliorated ferroptosis‐induced cardiomyocyte death as evidenced by the increased cell viability, the reduced reactive oxygen species (ROS) generation, lactate dehydrogenase (LDH) activity, malondialdehyde (MDA) and Fe2+ contents, and the up‐regulated glutathione (GSH)/glutathione disulphide (GSSG) ratio as well as glutathione peroxidase 4 (Gpx4) protein expression in H9c2 cells‐exposed to OGD/R, while miR‐199a‐5p mimic had the opposite effects. In addition, OGD/R led to the inhibition of Akt/eNOS signaling pathway, which was also blocked by miR‐199a‐5p inhibitor and aggravated by miR‐199a‐5p mimic. Furthermore, LY294002, an inhibitor of Akt/eNOS signaling pathway, abrogated miR‐199a‐5p inhibitor‐induced the reduction of ferroptosis‐induced cardiomyocyte death. In summary, our findings demonstrated that miR‐199a‐5p plays a central role in stimulating ferroptosis‐induced cardiomyocyte death during ischemic/hypoxic injury via inhibiting Akt/eNOS signaling pathway.

Keywords