MiR214-3p Ameliorates Diabetic Cardiomyopathy by Inhibiting Ferroptosis.

Abstract

Ferroptosis is involved in the pathogenesis of diabetic cardiomyopathy (DCM). It has been shown that miR214-3p regulates ferroptosis, but no studies have shown a relationship between miR214-3p and DCM. This study induced glucolipotoxicity cardiomyocytes by treating HL-1 with high glucose and palmitic acid. Under these conditions, intracellular proteins TfR1 and FTH1, involved in Fe²⁺ transport and storage, were significantly elevated, and intracellular Fe²⁺ deposition was increased. The expression of GPX4, a key antioxidant molecule in ferroptosis, was reduced considerably, and the expression of lipid peroxidation-related proteins ACSL4 and COX2 was significantly elevated, with increased intracellular lipid peroxidation. Glucolipotoxicity cardiomyocytes overexpressing miR214-3p showed reduced expression levels of intracellular iron metabolism-related proteins, decreased Fe²⁺ deposition, elevated GPX4 expression, markedly down-regulated expression of ACSL4 and COX2, and reduced intracellular lipid peroxidation. In contrast, glucolipotoxicity cardiomyocytes with knockdown of miR214-3p showed more severe Fe²⁺ deposition and lipid peroxidation. In vivo, DCM mice showed significant cardiac function reduction and myocardial fibrosis. Consistent with the in vitro experiments, the expression level of GPX4 in myocardial tissues of DCM mice was reduced, and the expression of FTH1, ACSL4, and COX2 was significantly elevated. In contrast, DCM mice treated with miR214-3p showed improved cardiac function and alleviated myocardial fibrosis, with up-regulated GPX4 protein expression levels and significantly suppressed FTH1, ACSL4, and COX2 expression. These findings revealed that miR214-3p inhibits ferroptosis to improve DCM.