Objective: Myocardial ischemia/reperfusion (MI/R) injury is a complicated pathophysiological process associated with cardiomyocyte pyroptosis. Methyltransferase-like protein 3 (METTL3) catalyzes the formation of N-methyl-adenosine (mA) and participates in various biological processes. This study probed into the mechanism of METTL3 in cardiomyocyte pyroptosis in MI/R injury.
Methods: A rat model of MI/R was established. Rat cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment for the establishment of a cell model in vitro. METTL3 expression in myocardial tissues of MI/R rats and OGD/R-treated cardiomyocytes was determined using RT-qPCR and Western blot. The pathological changes of rat myocardial tissues were observed using hematoxylin and eosin staining. The positive expression of NLRP3 in myocardial tissues or cardiomyocytes was observed through immunohistochemistry or immunofluorescence. The activity of caspase-1 was measured using the colorimetric method. The expressions of GSDMD and cleaved caspase-1, as well as the levels of IL-1β and IL-18 in rat myocardial tissues or cardiomyocytes were determined. mA modification level was quantified. The binding relationship between pri-miR-143-3p and DGCR8 and the enrichment of mA on pri-miR-143-3p were detected. The binding relationship between miR-143-3p and protein kinase C epsilon (PRKCE) was verified.
Results: METTL3 expression was elevated in MI/R rats and OGD/R cardiomyocytes. METTL3 silencing alleviated myocardial injury, reduced the number of NLRP3-positive cardiomyocytes, suppressed caspase-1 activity, decreased the protein levels of GSDMD-N and cleaved caspase-1, and decreased IL-1β and IL-18 levels. METTL3 increased the total mA level in MI/R rats and injured cardiomyocytes, promoted DGCR8 binding to pri-miR-143-3p, and enhanced miR-143-3p expression. miR-143-3p suppressed PRKCE transcription, and miR-143-3p overexpression reversed the inhibitory effect of METTL3 silencing on cardiomyocyte pyroptosis.
Conclusion: METTL3 promoted DGCR8 binding to pri-miR-143-3p through mA modification, thus enhancing miR-143-3p expression to inhibit PRKCE transcription and further aggravating cardiomyocyte pyroptosis and MI/R injury.
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