MALAT1-mediated recruitment of the histone methyltransferase EZH2 to the microRNA-22 promoter leads to cardiomyocyte apoptosis in diabetic cardiomyopathy

Diabetic patients often have a heightened risk of cardiomyopathy, even in the absence of traditional risk factors such as hypertension and atherosclerotic coronary artery disease. Diabetic cardiomyopathy is characterized by a typical cardiomyopathy specific to diabetes, the pathogenesis of which has yet to be fully elucidated. As a well-documented oncogenic long noncoding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been implicated in a variety of pathological processes, including diabetic complications. This study aimed to evaluate the functional roles of MALAT1 in the pathogenesis of diabetic cardiomyopathy. Spontaneously diabetic (db/db) C57BL/Ks mice were employed to establish diabetic cardiomyopathy models in vivo and high glucose (HG)-cultured mouse cardiomyocytes for myocardial damage models in vitro. Mouse left ventricular volume and function were evaluated by echocardiography, while the myocyte cross-sectional area was calculated to evaluate the degree of myocardial hypertrophy. TUNEL staining and flow cytometric analysis were performed to evaluate myocardial damage and cardiomyocyte apoptosis. Silencing of MALAT1 was found to attenuate cardiac dysfunction and inhibit cardiomyocyte apoptosis in db/db mice and HG-cultured mouse cardiomyocytes. MALAT1 recruited the histone methyltransferase EZH2 to the miR-22 promoter region and inhibited its expression. EZH2 induced an increased in the expression of ATP-binding cassette transporter A1 (ABCA1), which was identified to be a target gene of miR-22. Silencing of EZH2 was found to improve cardiac function and prevent cardiomyocyte apoptosis in db/db mice and HG-cultured mouse cardiomyocytes in the presence of MALAT1, suggesting that MALAT1 mediated myocardial damage by recruiting EZH2 to the miR-22 promoter. Taken together, this study's findings provide evidence confirming our hypothesis, suggesting the involvement of MALAT1 in the processes of cardiac function and cardiomyocyte apoptosis via the EZH2/miR-22/ABCA1 signaling cascade, which has potential therapeutic implications for the understanding of diabetic cardiomyopathy.