Inhibition of miR-214-3p attenuates ferroptosis in myocardial infarction via regulating ME2

Myocardial infarction (MI) contributes to an increased risk of incident heart failure and sudden death, but there is still a lack of effective treatment in clinic. Recently, growing evidence has indicated that abnormal expression of microRNAs (miRNAs) plays a crucial role in cardiovascular diseases. In this research, the involvement of miRNA-214-3p in MI was explored. A mouse model of MI was established by ligation of the left anterior descending coronary artery, and primary cultures of neonatal rat car-diomyocytes (NRCMs) were submitted to hypoxic treatment to stimulate cellular injury in vitro. Our results showed that miR-214-3p level was significantly upregulated in the infarcted region of mouse hearts and in NRCMs exposed to hypoxia, accompanying with an obvious elevation of ferroptosis. In-hibition of miR-214-3p by antagomir injection improved cardiac function, decreased infarct size, and attenuated iron accumulation and oxidant stress in myocardial tissues. MiR-214-3p could also promote ferroptosis and cellular impairments in NRCMs, while miR-214-3p inhibitor effectively protected cells from hypoxia. Furthermore, dual luciferase reporter gene assay revealed that malic enzyme 2 (ME2) is a direct target of miR-214-3p. In cardiomyocytes, overexpression of ME2 ameliorated the detrimental ef-fects and excessive ferroptosis induced by miR-214-3p mimic, whereas ME2 depletion compromised the protective role of miR-214-3p inhibitor against hypoxic injury and ferroptosis. These findings suggest that miR-214-3p contributes to enhanced ferroptosis during MI at least partially via suppressing ME2. Inhibition of miR-214-3p may be a new approach for tackling MI.(c) 2023 Elsevier Inc. All rights reserved.

Automated summary

Myocardial infarction (MI) increases the risk of heart failure and sudden death, but effective treatments are still lacking in clinical practice. Abnormal expression of microRNAs (miRNAs) has been found to play a crucial role in cardiovascular diseases. This study investigated the involvement of miRNA-214-3p in MI. The results showed that miR-214-3p was significantly upregulated in the infarcted region in mouse hearts and in hypoxia-exposed rat cardiomyocytes, which was accompanied by increased ferroptosis. Inhibition of miR-214-3p improved cardiac function, reduced infarct size, and attenuated iron accumulation and oxidant stress. MiR-214-3p could promote ferroptosis and cellular impairments, while its inhibition protected cells from hypoxic injury. Furthermore, malic enzyme 2 (ME2) was identified as a direct target of miR-214-3p. Overexpression of ME2 ameliorated the detrimental effects induced by miR-214-3p mimic, while its depletion compromised the protective role of miR-214-3p inhibitor. These findings suggest that miR-214-3p contributes to enhanced ferroptosis during MI by suppressing ME2. Inhibition of miR-214-3p may represent a novel approach for treating MI.