Diabetes blocks the cardioprotective effects of sevoflurane postconditioning by impairing Nrf2/Brg1/HO-1 signaling

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• 作者：Sumin Gao^a ; Zhengchao Yang^a ; Ruili Shi^a ; Dan Xu^a ; Haobo Li^b ; Zhengyuan Xia^b ; Qing-ping Wu^a ; Shanglong Yao^a ; Tingting Wang^a ; ^{wangtt201307@163.com" class="auth_mail" title="E-mail the corresponding author} ; Shiying Yuan^a ; ^{yuan_shiying@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Sevoflurane ; Postconditioning ; Diabetes ; Nrf2 ; Brg1 ; HO-1
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：15 May 2016
• 年：2016
• 卷：779
• 期：Complete
• 页码：111-121
• 全文大小：5214 K

文摘

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 45 min coronary artery occlusion followed by 2 h reperfusion with or without SPostC achieved by exposing the mice to 2% sevoflurane for 15 min at the onset of reperfusion. In invitro study, H9c2 cells were exposed to normal or high glucose and subjected to 3 h hypoxia followed by 6 h 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.