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Dihydromyricetin Prevents Diabetic Cardiomyopathy via miR-34a Suppression by Activating Autophagy

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Abstract

Purpose

The pro-aging miRNA, miR-34a, is hyperactivated in the cardiac myocardial tissues of patients and mice with diabetes, leading to diabetic cardiomyopathy (DCM). Increasing evidence suggests that dihydromyricetin (DHM) can be used to effectively treat cardiomyopathy. In this study, we investigated whether DHM affects the expression of miR-34a in DCM.

Methods

The expression of miR-34a in high-glucose-induced cardiomyocytes and in the heart tissue of diabetic mice was determined by microRNA isolation and quantitative reverse transcription-polymerase chain reaction. Lipofectamine 3000 was used to transfect cardiomyocytes with miR-34a inhibitor, miR-34a mimics, and miR-control. These agents were intravenously injected into the tail vein of streptozotocin-induced diabetic mice. Autophagy and apoptosis were assessed in high-glucose-induced cardiomyocytes and cardiac tissue in diabetic mice by western blotting, immunofluorescence, Masson staining, hematoxylin and eosin staining (H&E), and electron microscopy.

Results

DHM clearly ameliorated the cardiac dysfunction in the diabetic mice. The expression of miR-34a was up-regulated in high-glucose-induced cardiomyocytes and in the hearts of diabetic mice, thus impairing autophagy. Treatment with DHM decreased the expression of miR-34a and rescued the impairment of autophagy in high-glucose-induced cardiomyocytes and in the heart tissue of diabetic mice, while the miR-34a mimic offset the effect of DHM with respect to the development of DCM by inhibiting autophagy.

Conclusions

By decreasing the expression of miR-34a, DHM restores impaired autophagy, and thus ameliorates DCM. Therefore, DHM may potentially be used in the treatment of DCM.

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Abbreviations

CON:

Control group

CON + DHM:

Control group fed DHM

DCM:

Diabetic cardiomyopathy

DHM:

Dihydromyricetin

DM:

Diabetic group

DM + DHM:

Diabetic group fed DHM

DM + DHM + miR-control:

Diabetic group fed DHM and administered miR-control via tail vein injection

DM + DHM + miR-34a inhibitor:

Diabetic group fed DHM and injected with miR-34a inhibitor

DM + DHM + miR-34a mimic:

Diabetic group fed DHM and administered miR-34a mimic via tail vein injection

H&E:

Hematoxylin and eosin

miRNA:

MicroRNA

T2D:

Type 2 diabetes mellitus

RT-PCR:

Reverse transcription-polymerase chain reaction

STZ:

Streptozotocin

TEM:

Transmission electron microscopy

HR:

Heart rate

LVEDD:

Left ventricular end-diastolic dimension

LVESD:

Left ventricular end-systolic dimension

LVEF:

Left ventricular ejection fraction

LVFS:

Left ventricular systolic function

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Acknowledgements

The authors thank the Faculty of Agriculture, Life and Environment Science at Zhejiang University for their valuable technical assistance.

Funding

This research was supported by grants from the National Natural Science Foundation of China (81873120), Social Development Project of Public Welfare Technology Application in Zhejiang Province (LGF19H020006).

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Authors and Affiliations

  1. Zhejiang University, Hangzhou, Zhejiang, China

    Tingjuan Ni, Na Lin, Wenqiang Lu, Zhenzhu Sun & Hui Lin

  2. Medical Research Center, Shaoxing People’s Hospital Shaoxing Hospital, Zhejiang University School of Medicine, No. 568 Zhongxing North Road, Shaoxing, Zhejiang, China

    Jufang Chi & Hangyuan Guo

Authors
  1. Tingjuan Ni
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  2. Na Lin
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  3. Wenqiang Lu
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Contributions

Tingjuan Ni conceived the study, acquired data, interpreted the results, and drafted the manuscript; Na Lin, Wenqiang Lu, and Zhenzhu Sun performed some experiments; Tingjuan Ni assisted technicians with animal sacrifice; Hui Lin determined the food composition; Jufang Chi, Hangyuan Guo, Tingjuan NI, and Na Lin approved the final version. Tingjuan Ni designed the study, interpreted the results and revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jufang Chi or Hangyuan Guo.

Ethics declarations

All animal protocols were approved by the Animal Care and Use Committee of the Shaoxing Hospital, Zhejiang University School of Medicine. All procedures performed in studies involving animals met the ethical standards of the institution or practice conducting the study.

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The authors have no conflict of interest.

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Ni, T., Lin, N., Lu, W. et al. Dihydromyricetin Prevents Diabetic Cardiomyopathy via miR-34a Suppression by Activating Autophagy. Cardiovasc Drugs Ther 34, 291–301 (2020). https://doi.org/10.1007/s10557-020-06968-0

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