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Diallyl trisulfide ameliorates myocardial ischemia–reperfusion injury by reducing oxidative stress and endoplasmic reticulum stress-mediated apoptosis in type 1 diabetic rats: role of SIRT1 activation

Abstract

Diallyl trisulfide (DATS) protects against apoptosis during myocardial ischemia-reperfusion (MI/R) injury in diabetic state, although the underlying mechanisms remain poorly defined. Previously, we and others demonstrated that silent information regulator 1 (SIRT1) activation inhibited oxidative stress and endoplasmic reticulum (ER) stress during MI/R injury. We hypothesize that DATS reduces diabetic MI/R injury by activating SIRT1 signaling. Streptozotocin (STZ)-induced type 1 diabetic rats were subjected to MI/R surgery with or without perioperative administration of DATS (40 mg/kg). We found that DATS treatment markedly improved left ventricular systolic pressure and the first derivative of left ventricular pressure, reduced myocardial infarct size as well as serum creatine kinase and lactate dehydrogenase activities. Furthermore, the myocardial apoptosis was also suppressed by DATS as evidenced by reduced apoptotic index and cleaved caspase-3 expression. However, these effects were abolished by EX527 (the inhibitor of SIRT1 signaling, 5 mg/kg). We further found that DATS effectively upregulated SIRT1 expression and its nuclear distribution. Additionally, PERK/eIF2α/ATF4/CHOP-mediated ER stress-induced apoptosis was suppressed by DATS treatment. Moreover, DATS significantly activated Nrf-2/HO-1 antioxidant signaling pathway, thus reducing Nox-2/4 expressions. However, the ameliorative effects of DATS on oxidative stress and ER stress-mediated myocardial apoptosis were inhibited by EX527 administration. Taken together, these data suggest that perioperative DATS treatment effectively ameliorates MI/R injury in type 1 diabetic setting by enhancing cardiac SIRT1 signaling. SIRT1 activation not only upregulated Nrf-2/HO-1-mediated antioxidant signaling pathway but also suppressed PERK/eIF2α/ATF4/CHOP-mediated ER stress level, thus reducing myocardial apoptosis and eventually preserving cardiac function.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81500263, 81470411 and 81570232).

Author contributions

The authors who participated in the research design were Liming Yu, Shu Li, Yang Yang and Huishan Wang. Liming Yu and Shu Li conducted experiments. Zhi Li, Jian Zhang, Xiaodong Xue, Liming Yu, Shu Li and Xinlong Tang performed the data analysis. Xinlong Tang, Liming Yu, Jinsong Han, Yu Liu, Yuji Zhang, Yong Zhang, Yinli Xu, Yang Yang and Huishan Wang wrote or contributed to the writing of the manuscript.

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Correspondence to Yang Yang or Huishan Wang.

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The authors declare that they have no competing interests.

Additional information

Liming Yu, Shu Li, and Xinlong Tang have contributed equally to this work.

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Yu, L., Li, S., Tang, X. et al. Diallyl trisulfide ameliorates myocardial ischemia–reperfusion injury by reducing oxidative stress and endoplasmic reticulum stress-mediated apoptosis in type 1 diabetic rats: role of SIRT1 activation. Apoptosis 22, 942–954 (2017). https://doi.org/10.1007/s10495-017-1378-y

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Keywords

  • Diallyl trisulfide
  • SIRT1
  • Type 1 diabetes
  • Myocardial ischemia-reperfusion
  • Oxidative stress
  • Endoplasmic reticulum stress