Isosorbide mononitrate inhibits myocardial fibrosis in diabetic rats by up-regulating exosomal MiR-378

Abstract

Purpose: To investigate the effect of isosorbide mononitrate on diabetic cardiomyopathy (DCM), and the potential mechanism of action. Methods: The effects of isosorbide mononitrate and isosorbide mononitrate + GW4869 on cardiac function and myocardial fibrosis in DCM rats were determined via hemodynamics, hematoxylin-eosin (H&E) staining and Masson staining. Exosomes were extracted from the serum, and the differential expressions of microribonucleic acids (miRNAs) related to myocardial fibrosis were determined by reverse transcription-polymerase chain reaction (qRT-PCR). Western blotting was performed to determine the effects of isosorbide mononitrate and isosorbide mononitrate + GW4869 on IGF1R/STAT3 signaling pathway. Results: Isosorbide mononitrate exerted a protective effect against DCM-induced cardiac dysfunction and myocardial fibrosis, while such a protective effect was suppressed by the exosome inhibitor GW4869 (p < 0.05). The expression of miR-378 in exosomes significantly rose in isosorbide mononitrate group. The increased expression of miR-378 in vitro inhibited the proliferation of primary myocardial fibroblasts, and reduced the expression of myocardial fibrosis markers (p < 0.05). Luciferase reporter assay data showed that miR-378 negatively regulated the expression of IGF1R by direct binding to IGF1R mRNA 3'-untranslated region (3'UTR). In primary myocardial fibroblasts, miR-378 mimic significantly reduced the protein expressions of IGF1R, p-STAT3/STAT3 and c-Myc (p < 0.05). Isosorbide mononitrate lowered the protein expressions of IGF1R, p-STAT3/STAT3 and c-Myc, but the inhibitory effect was weakened by the exosome inhibitor, GW4869 (p < 0.05). Conclusion: Isosorbide mononitrate inhibits myocardial fibrosis in diabetic rats by up-regulating exosomal miR-378, and targeting the axis of STAT3/IGF1R. The results of this study may provide a new insight into the treatment of DCM.