• Sumin Gao, Zhengchao Yang, Ruili Shi, Dan Xu, Haobo Li, Zhengyuan Xia, Qing-Ping Wu, Shanglong Yao, Tingting Wang, and Shiying Yuan.
• Department of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
• Eur. J. Pharmacol. 2016 May 15; 779: 111-21.

AbstractSevofluane 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. Copyright © 2016 Elsevier B.V. All rights reserved.

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