The Protective Role of Bmal1-Regulated Autophagy Mediated by HDAC3/SIRT1 Pathway in Myocardial Ischemia/Reperfusion Injury of Diabetic Rats

Abstract

Purpose

Histone deacetylase 3 (HDAC3) and silent information regulator 1 (SIRT1) are histone deacetylases that regulate important metabolic pathways and play important roles in diabetes and myocardial ischemia/reperfusion (IR) injury. In this study, we explored the protective mechanism of Bmal1-regulated autophagy mediated by the HDAC3/SIRT1 pathway in myocardial IR injury of diabetic rats.

Methods and results

Type 1 diabetes was established by administering an intraperitoneal injection of streptozotocin. After 8 weeks, the left anterior descending coronary artery was ligated for 30 min and reperfused for 120 min to establish a myocardial IR injury model in diabetic rats. H9c2 cardiomyocytes were exposed to high glucose concentration (30 mM) and hypoxia/reoxygenation (H/R) stimulation in vitro. The myocardial infarct size and levels of serum cTn-I, CK-MB, and LDH in diabetic rats subjected to myocardial IR injury were significantly higher. Upregulated HDAC3 and downregulated SIRT1 expression were observed in diabetic and IR hearts, along with a lower Bmal1 level. Autophagy was rapidly increased in the hearts of diabetic or non-diabetic rats in the IR group compared with the sham group, but significantly attenuated in the hearts of diabetic rats compared with the hearts of non-diabetic rats after IR insult. Consistent with decreased autophagy, we observed increased HDAC3 expression and decreased SIRT1 and Bmal1 levels in the myocardial tissue of diabetic rats after IR. Inhibition of HDAC3 by the inhibitor RGFP966 and activation of SIRT1 by the agonist SRT1720 could significantly attenuate myocardial IR injury in diabetic rats by restoring Bmal1-regulated autophagy.

Conclusion

Based on these findings, the disordered HDAC3/SIRT1 circuit (upregulated HDAC3 and downregulated SIRT1 levels) plays an important role in aggravating myocardial IR injury in diabetic rats by downregulating Bmal1-mediated autophagy. Treatments targeting HDAC3/SIRT1 to activate the autophagy may represent a novel strategy to alleviate myocardial IR injury in diabetes.

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Data Availability

The used and/or analyzed datasets are available from the corresponding author on reasonable request.

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Funding

This study was supported by grants from the National Natural Science Foundation of China (81970722 and 81671891).

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Authors

Contributions

Conceptualization: Z.Q. and Z.X.; methodology: Z.Q., H.M., and Y.Y; software: Z.Q. and Y.Z.; validation: Z.Q., H.M., and Y.Z.; formal analysis: Z.Q.; investigation: S.L.; resources: Z.X.; data curation: Z.Q. and H.M.; writing—original draft preparation: Z.Q.; writing—review and editing: S.L. and Z.X.; visualization: Z.Q.; supervision: Z.X.; project administration: S.L. and Z.X.; funding acquisition: Z.X. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Shaoqing Lei or Zhong-yuan Xia.

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The care of animals and all animal experiments were implemented after being reviewed and approved by the Laboratory Animal Welfare & Ethics Committee (IACUC) of Renmin Hospital of Wuhan University.

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Qiu, Z., Ming, H., Zhang, Y. et al. The Protective Role of Bmal1-Regulated Autophagy Mediated by HDAC3/SIRT1 Pathway in Myocardial Ischemia/Reperfusion Injury of Diabetic Rats. Cardiovasc Drugs Ther (2021). https://doi.org/10.1007/s10557-021-07159-1

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Keywords

  • HDAC3
  • SIRT1
  • Bmal1
  • Autophagy
  • Myocardial ischemia reperfusion injury