Abstract
In the previous study, we generated a rat model of dilated cardiomyopathy (DCM) induced by adriamycin and found that the expression of lncRNA H19 was significantly upregulated in myocardial tissue. The present study was aimed to investigate the potential role of H19 in the pathogenesis of adriamycin-induced DCM. H19 knockdown in the myocardium of DCM rats attenuated cardiomyocyte apoptosis and improved left ventricular structure and function. Adriamycin treatment was associated with elevated H19 and miR-675 expression and increased apoptosis in neonatal cardiomyocytes. Enforced expression of miR-675 was found to induce apoptosis in cardiomyocytes with adriamycin treatment and H19-siRNA transfection. The 3′-untranslated region of PA2G4 was cloned downstream of a luciferase reporter construct and cotransfected into HEK293 cells with miR-675 mimic. The results of luciferase assay showed that PA2G4 was a direct target of miR-675. The expression of PA2G4 was reduced in cardiomyocytes transfected with miR-675 mimic. Moreover, H19 knockdown was found to increase PA2G4 expression and suppress apoptosis in cardiomyocytes exposed to adriamycin. In conclusion, our study suggests that H19/miR-675 axis is involved in the promotion of cardiomyocyte apoptosis by targeting PA2G4, which may provide a new therapeutic strategy for the treatment of adriamycin-induced DCM.
Highlights
Dilated cardiomyopathy (DCM) is characterized by ventricular enlargement and systolic dysfunction with reduced ventricular wall thickness [1]
We generated a rat model of dilated cardiomyopathy (DCM) induced by adriamycin and found that the expression of Long non-coding RNAs (lncRNAs) H19 was significantly upregulated in myocardial tissue
Our study suggests that H19/miR-675 axis is involved in the promotion of cardiomyocyte apoptosis by targeting PA2G4, which may provide a new therapeutic strategy for the treatment of adriamycin-induced DCM
Summary
Dilated cardiomyopathy (DCM) is characterized by ventricular enlargement and systolic dysfunction with reduced ventricular wall thickness [1]. It is a common cause of sudden cardiac death and congestive heart failure. Adriamycin has been found to increase oxidative stress, reduce ATP production, alter gene expression, and induce mitochondrial abnormality as well as cardiomyocyte apoptosis, which are critically involved in the pathogenesis of DCM [2]. Long non-coding RNAs (lncRNAs) are transcribed RNA molecules longer than 200 nucleotides without protein-coding function. They can regulate gene expression at the epigenetic, transcriptional and post-transcriptional levels and can actively participate in various physiological and pathological processes [3]. The present study was designed to investigate the pathogenic role of H19 in adriamycin-induced DCM
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