lncRNA H19/miR-675 axis regulates cardiomyocyte apoptosis by targeting VDAC1 in diabetic cardiomyopathy

Abstract

We previously established a rat model of diabetic cardiomyopathy (DCM) and found that the expression of lncRNA H19 was significantly downregulated. The present study was designed to investigate the pathogenic role of H19 in the development of DCM. Overexpression of H19 in diabetic rats attenuated oxidative stress, inflammation and apoptosis, and consequently improved left ventricular function. High glucose was associated with reduced H19 expression and increased cardiomyocyte apoptosis. To explore the molecular mechanisms involved, we performed in vitro experiments using cultured neonatal rat cardiomyocytes. Our results showed that miR-675 expression was decreased in cardiomyocytes transfected with H19 siRNA. The 3′UTR of VDAC1 was cloned downstream of a luciferase reporter construct and cotransfected into HEK293 cells with miR-675 mimic. The results of luciferase assay indicated that VDAC1 might be a direct target of miR-675. The expression of VDAC1 was upregulated in cardiomyocytes transfected with miR-675 antagomir, which consequently promotes cellular apoptosis. Moreover, enforced expression of H19 was found to reduce VDAC1 expression and inhibit apoptosis in cardiomyocytes exposed to high glucose. In conclusion, our study demonstrates that H19/miR-675 axis is involved in the regulation of high glucose-induced apoptosis by targeting VDAC1, which may provide a novel therapeutic strategy for the treatment of DCM.

LncRNA KCNQ1OT1 Mediates Pyroptosis in Diabetic Cardiomyopathy

“…For example, the lncRNA H19 is downregulated in DCM and influences apoptosis via miR-675 and VDAC1 [21]. The lncRNA MIAT is upregulated in high glucose-treated cardiomyocytes and STZ-induced mice, and it sponges miR-22-3p to regulate DAPK2 expression [22].…”

Of mice and men: models and mechanisms of diabetic cardiomyopathy

“…Similarly to miRNAs, lncRNAs contribute to the development of DCM [121, 127]. Circulating lncRNAs predict LV diastolic function and remodelling in patients with T2D [59].…”

Microarray Analysis of Long Noncoding RNAs in Female Diabetic Peripheral Neuropathy Patients

“…Acting as a molecular sponge, the decreased expression of H19 leads to the increased bioavailability of miR-let-7, causing diminished expression of miR-let-7 targets, which results in impaired insulin signaling and glucose metabolism [29]. Moreover, H19 acts as the precursor of miR-675, and the latter, through the down-regulation of its target gene VDAC1 (voltagedependent anion channel 1), regulates cardiomyocyte apoptosis in the pathogenesis of diabetic cardiomyopathy [30]. Unlike previous studies, the present microarray analysis was conducted in PBMCs, and the expression level of H19 decreased significantly only in the DPN group.…”