title: Cardioprotection from emulsified isoflurane postconditioning is lost in rats with streptozotocin-induced diabetes due to the impairment of Brg1/Nrf2/STAT3 signalling.
abstract: Isoflurane postconditioning (IsoPostC) attenuates myocardial ischaemia/reperfusion injury (IRI). Signal transducer and activator of transcription-3 (STAT3) is critical in ischaemic postconditioning cardioprotection, which can be regulated by the Brahma-related gene (Brg1) and nuclear factor-erythroid 2-related factor 2 (Nrf2), although they are both reduced in diabetic hearts. We hypothesized that reduced Brg1/Nrf2 and STAT3 activation may jeopardize IsoPostC-mediated cardioprotection in diabetic hearts. In the present study, Langendorff-perfused, non-diabetic (control) and 8-week-old streptozotocin-induced Type 1 diabetic rat hearts were subjected to 30 min of global ischaemia and 120 min of reperfusion without or with IsoPostC, which was achieved by administering emulsified isoflurane (2.0%, v/v) in Krebs-Henseleit (KH) solution immediately at the onset of reperfusion for 10 min and switching to KH solution perfusion alone thereafter. Cultured H9C2 cells were exposed to normal glucose (NG, 5.5 mM) or high glucose (HG, 30 mM) and subjected to hypoxia/reoxygenation (HR) in the presence or absence of IsoPostC. Diabetic rats displayed larger post-ischaemic myocardial infarction and more severe haemodynamic dysfunction, associated with increased myocardial oxidative stress and reduced cardiac Brg1, Nrf2 and STAT3 phosphorylation/activation (p-STAT3), compared with controls. These changes were reversed/prevented by IsoPostC in control but not in diabetic rats. In H9C2 cells exposed to NG but not HG, IsoPostC significantly attenuated HR-induced cellular injury and superoxide anion production with increased Brg1, Nrf2 and p-STAT3. These beneficial effects of IsoPostC were abolished by Brg1, Nrf2 or STAT3 gene knockdown. Brg1 or Nrf2 gene knockdown abolished IsoPostC-induced STAT3 activation. N-acetylcysteine restored Brg1, Nrf2 and p-STAT3, and IsoPostC-induced protection in H9C2 cells exposed to HG and HR. In conclusion, IsoPostC confers cardioprotection through Brg1/Nrf2/STAT3 signalling, and impairment of this pathway may be responsible for the loss of IsoPostC cardioprotection in diabetes.
authors: Department of Anaesthesiology, University of Hong Kong, Hong Kong SAR, China.
authors: Yan
authors: Y
authors: Wang
authors: Department of Anaesthesiology, University of Hong Kong, Hong Kong SAR, China State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong SAR, China.
authors: Haobo
authors: H
authors: Li
authors: Department of Anaesthesiology, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors: Huansen
authors: H
authors: Huang
authors: Department of Anaesthesiology, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors: Shiming
authors: S
authors: Liu
authors: Department of Anaesthesiology, University of Hong Kong, Hong Kong SAR, China.
authors: Xiaowen
authors: X
authors: Mao
authors: Department of Anaesthesiology, Guangdong Cardiovascular Institute and Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors: Sheng
authors: S
authors: Wang
authors: Department of Anaesthesiology, University of Hong Kong, Hong Kong SAR, China.
authors: Stanley Sau-Ching
authors: SS
authors: Wong
authors: Department of Anaesthesiology, University of Hong Kong, Hong Kong SAR, China State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong SAR, China zyxia@hku.hk mgirwin@hku.hk.
authors: Zhengyuan
authors: Z
authors: Xia
authors: Department of Anaesthesiology, University of Hong Kong, Hong Kong SAR, China zyxia@hku.hk mgirwin@hku.hk.
authors: Michael G
authors: MG
authors: Irwin
mesh_terms: D000818:Animals; D004265:DNA Helicases / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy*; D004195:Disease Models, Animal; D057775:Ischemic Postconditioning / Q000379:methods; D007530:Isoflurane / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013311:Streptozocin; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D009687:Nuclear Proteins; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D014157:Transcription Factors; D013311:Streptozocin; D007530:Isoflurane; C578929:Smarca4 protein, rat; D004265:DNA Helicases
keywords: Brg1; Nrf2; STAT3; diabetes; ischaemia/reperfusion injury; isoflurane postconditioning