Resveratrol-enhanced autophagic flux ameliorates myocardial oxidative stress injury in diabetic mice
Article first published online: 1 JUN 2014
© 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
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Journal of Cellular and Molecular Medicine
Volume 18, Issue 8, pages 1599–1611, August 2014
How to Cite
Wang, B., Yang, Q., Sun, Y.-y., Xing, Y.-f., Wang, Y.-b., Lu, X.-t., Bai, W.-w., Liu, X.-q. and Zhao, Y.-x. (2014), Resveratrol-enhanced autophagic flux ameliorates myocardial oxidative stress injury in diabetic mice. Journal of Cellular and Molecular Medicine, 18: 1599–1611. doi: 10.1111/jcmm.12312
- Issue published online: 2 SEP 2014
- Article first published online: 1 JUN 2014
- Manuscript Accepted: 31 MAR 2014
- Manuscript Received: 17 DEC 2013
- National 973 Basic Research Program of China. Grant Number: 2012CB518603
- National Natural Science Foundation of China. Grant Numbers: 81100103, 30873325, 81173251
- Natural Science Foundation of Shandong Province. Grant Number: ZR2011HQ020
- oxidative stress
Autophagic dysfunction is observed in diabetes mellitus. Resveratrol has a beneficial effect on diabetic cardiomyopathy. Whether the resveratrol-induced improvement in cardiac function in diabetes is via regulating autophagy remains unclear. We investigated the mechanisms underlying resveratrol-mediated protection against heart failure in diabetic mice, with a focus on the role of sirtuin 1 (SIRT1) in regulating autophagic flux. Diabetic cardiomyopathy in mice was induced by streptozotocin (STZ). Long-term resveratrol treatment improved cardiac function, ameliorated oxidative injury and reduced apoptosis in the diabetic mouse heart. Western blot analysis revealed that resveratrol decreased p62 protein expression and promoted SIRT1 activity and Rab7 expression. Inhibiting autophagic flux with bafilomycin A1 increased diabetic mouse mortality and attenuated resveratrol-induced down-regulation of p62, but not SIRT1 activity or Rab7 expression in diabetic mouse hearts. In cultured H9C2 cells, redundant or overactive H2O2 increased p62 and cleaved caspase 3 expression as well as acetylated forkhead box protein O1 (FOXO1) and inhibited SIRT1 expression. Sirtinol, SIRT1 and Rab7 siRNA impaired the resveratrol amelioration of dysfunctional autophagic flux and reduced apoptosis under oxidative conditions. Furthermore, resveratrol enhanced FOXO1 DNA binding at the Rab7 promoter region through a SIRT1-dependent pathway. These results highlight the role of the SIRT1/FOXO1/Rab7 axis in the effect of resveratrol on autophagic flux in vivo and in vitro, which suggests a therapeutic strategy for diabetic cardiomyopathy.