title: Resveratrol-enhanced autophagic flux ameliorates myocardial oxidative stress injury in diabetic mice.
abstract: 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.
authors.affiliation: Department of Traditional Chinese Medicine, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.forename: Yuan-yuan
authors.initials: YY
authors.lastname: Sun
authors.forename: Yi-fan
authors.initials: YF
authors.lastname: Xing
authors.forename: Ying-bin
authors.initials: YB
authors.lastname: Wang
authors.forename: Xiao-ting
authors.initials: XT
authors.lastname: Lu
authors.forename: Wen-wu
authors.initials: WW
authors.lastname: Bai
authors.forename: Xiao-qiong
authors.initials: XQ
authors.lastname: Liu
authors.forename: Yu-xia
authors.initials: YX
authors.lastname: Zhao
mesh_terms: D000107:Acetylation; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000503:physiopathology*; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D000975:Antioxidants; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013267:Stilbenes; D000090802:rab7 GTP-Binding Proteins; C000716465:rab7 GTP-binding proteins, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D020691:rab GTP-Binding Proteins; D000077185:Resveratrol
keywords: autophagy; cardiomyocyte; diabetes; oxidative stress