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.
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May 2016
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Paraffin section of knee joint from CIA mouse model. Safranin-O/fast green staining showed significant cartilage degeneration and bone erosion in femorotibial joint. For further details see pp. 667-681. Image kindly provided by Dr. Chih-Hsin Tang.
Research Article|
April 01 2016
Cardioprotection from emulsified isoflurane postconditioning is lost in rats with streptozotocin-induced diabetes due to the impairment of Brg1/Nrf2/STAT3 signalling
Yan Wang;
Yan Wang
1
*Department of Anaesthesiology, University of Hong Kong, Hong Kong SAR, China
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Haobo Li;
Haobo Li
1
*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
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Huansen Huang;
Huansen Huang
‡Department of Anaesthesiology, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Shiming Liu;
Shiming Liu
‡Department of Anaesthesiology, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Xiaowen Mao;
Xiaowen Mao
*Department of Anaesthesiology, University of Hong Kong, Hong Kong SAR, China
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Sheng Wang;
Sheng Wang
§Department of Anaesthesiology, Guangdong Cardiovascular Institute and Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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Stanley Sau-ching Wong;
Stanley Sau-ching Wong
*Department of Anaesthesiology, University of Hong Kong, Hong Kong SAR, China
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Zhengyuan Xia;
*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
Correspondence: Dr Zhengyuan Xia ([email protected]) or Professor Michael G. Irwin ([email protected]).
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Michael G. Irwin
*Department of Anaesthesiology, University of Hong Kong, Hong Kong SAR, China
Correspondence: Dr Zhengyuan Xia ([email protected]) or Professor Michael G. Irwin ([email protected]).
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Publisher: Portland Press Ltd
Received:
September 01 2015
Revision Received:
February 04 2016
Accepted:
February 04 2016
Accepted Manuscript online:
February 04 2016
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 Authors; published by Portland Press Limited
2016
Clin Sci (Lond) (2016) 130 (10): 801–812.
Article history
Received:
September 01 2015
Revision Received:
February 04 2016
Accepted:
February 04 2016
Accepted Manuscript online:
February 04 2016
Citation
Yan Wang, Haobo Li, Huansen Huang, Shiming Liu, Xiaowen Mao, Sheng Wang, Stanley Sau-ching Wong, Zhengyuan Xia, Michael G. Irwin; Cardioprotection from emulsified isoflurane postconditioning is lost in rats with streptozotocin-induced diabetes due to the impairment of Brg1/Nrf2/STAT3 signalling. Clin Sci (Lond) 1 May 2016; 130 (10): 801–812. doi: https://doi.org/10.1042/CS20150617
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