Abstract
Aim: Vildagliptin (vild) improves diastolic dysfunction and is associated with a lower relative risk of major adverse cardiovascular events in younger patients. The present study aimed to evaluate whether vild prevents the development of diabetic cardiomyopathy in type 2 diabetic mice and identify its underlying mechanisms. Methods: Type 2 diabetic mouse model was generated using wild-type (WT) (C57BL/6J) and miR-21 knockout mice by treatment with HFD/STZ. Cardiomyocyte-specific miR-21 overexpression was achieved using adeno-associated virus 9. Echocardiography was used to evaluate cardiac function in mice. Morphology, autophagy, and proteins levels in related pathway were analyzed. qRT-PCR was used to detect miR-21. Rat cardiac myoblast cell line (H9c2) cells were transfected with miR-21 mimics and inhibitor to explore the related mechanisms of miR-21 in diabetic cardiomyopathy. Results: Vild restored autophagy and alleviated fibrosis, thereby enhancing cardiac function in DM mice. In addition, miR-21 levels were increased under high glucose conditions. miR-21 knockout DM mice with miR-21 knockout had reduced cardiac hypertrophy and cardiac dysfunction compared to WT DM mice. Overexpression of miR-21 aggravated fibrosis, reduced autophagy, and attenuated the protective effect of vild on cardiac function. In high-glucose-treated H9c2 cells, the downstream effectors of sprouty homolog 1 (SPRY1) including extracellular signal-regulated kinases (ERK) and mammalian target of rapamycin showed significant changes following transfection with miR-21 mimics or inhibitor. Conclusion: The results of our study indicate that vild prevents DCM by restoring autophagy through the miR-21/SPRY1/ERK/mTOR pathway. Therefore, miR-21 is a target in the development of DCM, and vild demonstrates significant potential for clinical application in prevention of DCM.
Highlights
Diabetes is one of the most common and fastest growing diseases worldwide that is estimated to affect 693 million adults by 2045 (Cho et al, 2018)
The MA control group did not show any apparent difference in H9c2 cells relative to the NG group (Figures 5A,B). These results suggest that the SPRY1/ERK/mTOR pathway was inhibited in H9c2 cells following HG treatment
The result of miR-21 m transfection was opposite to that of mir21i transfection (Figures 5E,F). These results indicate that miR21 regulates autophagy through the SPRY1/ERK/mTOR pathway
Summary
Diabetes is one of the most common and fastest growing diseases worldwide that is estimated to affect 693 million adults by 2045 (Cho et al, 2018). Cardiovascular disease is the leading cause of death in diabetic patients, with approximately 70% mortality due to coronary artery disease. Despite normal coronary state and blood pressure, heart failure occurs in a subset of diabetic patients and is clinically characterized as diabetic cardiomyopathy (DCM) (Poornima et al, 2006). The data from the Framingham study suggest that diabetes is another discrete cause of congestive heart failure and that some form of cardiomyopathy is associated with diabetes (Kannel et al, 1974). DCM should be under intensive clinical focus
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