IPO (ischaemic post-conditioning) is a promising method of alleviating myocardial IR (ischaemia-reperfusion) injury; however, IPO-mediated cardioprotection is lost in diabetic hearts via mechanisms that remain largely unclear. We hypothesized that decreased cardiac expression of DJ-1, a positive modulator of autophagy, compromises the effectiveness of IPO-induced cardioprotection in diabetic rats. Diabetic rats subjected to myocardial IR (30 min of coronary artery occlusion followed by 120 min of reperfusion) exhibited more severe myocardial injury, less cardiac autophagy, lower DJ-1 expression and AMPK (adenosine monophosphate-activated protein kinase)/mTOR (mammalian target of rapamycin) pathway activity than non-diabetic rats. IPO significantly attenuated myocardial injury and up-regulated cardiac DJ-1 expression, AMPK/mTOR activity and autophagy in non-diabetic rats but not in diabetic rats. AAV9 (adeno-associated virus 9)-mediated cardiac DJ-1 overexpression as well as pretreatment with the autophagy inducer rapamycin restored IPO-induced cardioprotection in diabetic rats, an effect accompanied by AMPK/mTOR activation and autophagy up-regulation. Combining HPO (hypoxic post-conditioning) with DJ-1 overexpression markedly attenuated HR (hypoxia-reoxygenation) injury in H9c2 cells with high glucose (HG, 30 mM) exposure, accompanied by AMPK/mTOR signalling activation and autophagy up-regulation. The DJ-1 overexpression-mediated preservation of HPO-induced cardioprotection was completely inhibited by the AMPK inhibitor compound C (CC) and the autophagy inhibitor 3-MA (3-methyladenine). Thus, decreased cardiac DJ-1 expression, which results in impaired AMPK/mTOR signalling and decreased autophagy, could be a major mechanism underlying the loss of IPO-induced cardioprotection in diabetes.
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June 2017
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The accompanying caption is: Image demonstrates a 3D reconstruction of the neurovascular unit in a hippocampal artery in the mouse brain. For further details, see article by Nizari et al in this issue, pages 1207-1214. Image kindly provided by Cheryl Hawkes.
Research Article|
May 22 2017
DJ-1 overexpression restores ischaemic post-conditioning-mediated cardioprotection in diabetic rats: role of autophagy
Bin Zhou;
Bin Zhou
1Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
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Shaoqing Lei;
Shaoqing Lei
1Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
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Rui Xue;
Rui Xue
1Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
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Yan Leng;
Yan Leng
1Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
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Zhengyuan Xia;
Zhengyuan Xia
2Department of Anesthesiology, University of Hong Kong, Hong Kong, China
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Zhong-Yuan Xia
1Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
Correspondence: Zhong-yuan Xia ([email protected])
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Publisher: Portland Press Ltd
Received:
January 18 2017
Revision Received:
April 05 2017
Accepted:
April 12 2017
Accepted Manuscript online:
April 12 2017
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2017
Clin Sci (Lond) (2017) 131 (11): 1161–1178.
Article history
Received:
January 18 2017
Revision Received:
April 05 2017
Accepted:
April 12 2017
Accepted Manuscript online:
April 12 2017
Citation
Bin Zhou, Shaoqing Lei, Rui Xue, Yan Leng, Zhengyuan Xia, Zhong-Yuan Xia; DJ-1 overexpression restores ischaemic post-conditioning-mediated cardioprotection in diabetic rats: role of autophagy. Clin Sci (Lond) 1 June 2017; 131 (11): 1161–1178. doi: https://doi.org/10.1042/CS20170052
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