title: Diabetes blocks the cardioprotective effects of sevoflurane postconditioning by impairing Nrf2/Brg1/HO-1 signaling.
abstract: Sevofluane postconditioning (SPostC) protects heart against ischemia/reperfusion injury. However, SPostC cardioprotection is lost in diabetes whose cardiac heme oxygenase-1 (HO-1) is reduced. Brahma-related gene 1 (Brg1) facilitates nuclear factor-erythroid-2-related factor-2 (Nrf2) to activate HO-1 to increase myocardial antioxidant capacity in response to oxidative stress. However, cardiac Brg1 is reduced in diabetes. We hypothesized that SPostC confers cardioprotection by activating HO-1 through Nrf2/Brg1 and that impaired Nrf2/Brg1/HO-1 in diabetes is responsible for the loss of SPostC. Control and streptozotocin-induced diabetic mice were subjected to 45min coronary artery occlusion followed by 2h reperfusion with or without SPostC achieved by exposing the mice to 2% sevoflurane for 15min at the onset of reperfusion. In invitro study, H9c2 cells were exposed to normal or high glucose and subjected to 3h hypoxia followed by 6h reoxygenation. Diabetic mice displayed larger post-ischemic infarct size, severer cardiomyocytes apoptosis, and increased oxidative stress concomitant with reduced HO-1, nuclear Nrf2 and Brg1 protein expression. These changes were prevented/reversed by SPostC in control but not in diabetic mice, and these beneficial effects of SPostC were abolished by HO-1 inhibition. In H9c2 cells exposed to normal glucose but not high glucose, SPostC significantly attenuated hypoxia/reoxygenation-induced cellular injury and oxidative stress with increased HO-1 and nuclear Nrf2. These SPostC beneficial effects were canceled by HO-1 inhibition. In conclusion, SPostC protects against myocardial ischemia/reperfusion injury through activation of Nrf2/Brg1/HO-1 signaling and impairment of this signaling may be responsible for the loss of SPostC cardioprotection in diabetes.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Sumin
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Ruili
authors.initials: R
authors.lastname: Shi
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, The University of Hong Kong, Hong Kong, China.
authors.forename: Haobo
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, The University of Hong Kong, Hong Kong, China.
authors.forename: Zhengyuan
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Qing-Ping
authors.initials: QP
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Shanglong
authors.initials: S
authors.lastname: Yao
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: wangtt201307@163.com.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: yuan_shiying@163.com.
authors.forename: Shiying
authors.initials: S
authors.lastname: Yuan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology; D002460:Cell Line; D004265:DNA Helicases / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D057775:Ischemic Postconditioning; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008738:Methyl Ethers / Q000494:pharmacology*; D051379:Mice; D017202:Myocardial Ischemia / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D000077149:Sevoflurane; D015398:Signal Transduction / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D008738:Methyl Ethers; D051267:NF-E2-Related Factor 2; D009687:Nuclear Proteins; D014157:Transcription Factors; D013481:Superoxides; D000077149:Sevoflurane; D008315:Malondialdehyde; D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase; C513194:Smarca4 protein, mouse; D004265:DNA Helicases
keywords: Brg1; Diabetes; HO-1; Nrf2; Postconditioning; Sevoflurane