PMID- 28404768 OWN - NLM STAT- MEDLINE DCOM- 20170814 LR - 20220408 IS - 1470-8736 (Electronic) IS - 0143-5221 (Linking) VI - 131 IP - 11 DP - 2017 Jun 1 TI - DJ-1 overexpression restores ischaemic post-conditioning-mediated cardioprotection in diabetic rats: role of autophagy. PG - 1161-1178 LID - 10.1042/CS20170052 [doi] AB - 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. CI - (c) 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society. FAU - Zhou, Bin AU - Zhou B AD - Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China. FAU - Lei, Shaoqing AU - Lei S AD - Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China. FAU - Xue, Rui AU - Xue R AD - Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China. FAU - Leng, Yan AU - Leng Y AD - Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China. FAU - Xia, Zhengyuan AU - Xia Z AD - Department of Anesthesiology, University of Hong Kong, Hong Kong, China. FAU - Xia, Zhong-Yuan AU - Xia ZY AD - Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China xiazhongyuan2005@aliyun.com. LA - eng PT - Journal Article DEP - 20170522 PL - England TA - Clin Sci (Lond) JT - Clinical science (London, England : 1979) JID - 7905731 RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - EC 3.1.2.- (PARK7 protein, rat) RN - EC 3.1.2.- (Protein Deglycase DJ-1) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - AMP-Activated Protein Kinases/metabolism MH - Animals MH - Autophagy/drug effects/*physiology MH - Cells, Cultured MH - Diabetes Mellitus, Experimental/*complications/metabolism/pathology MH - Gene Expression Regulation MH - Genetic Therapy/methods MH - Genetic Vectors MH - Ischemic Postconditioning/*methods MH - Male MH - Myocardial Reperfusion Injury/etiology/metabolism/pathology/*prevention & control MH - Protein Deglycase DJ-1/genetics/*physiology MH - Rats, Sprague-Dawley MH - Signal Transduction/physiology MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases/metabolism OTO - NOTNLM OT - AMPK/mTOR pathway OT - DJ-1 OT - autophagy OT - diabetes OT - ischaemic post-conditioning EDAT- 2017/04/14 06:00 MHDA- 2017/08/15 06:00 CRDT- 2017/04/14 06:00 PHST- 2017/01/18 00:00 [received] PHST- 2017/04/05 00:00 [revised] PHST- 2017/04/12 00:00 [accepted] PHST- 2017/04/14 06:00 [pubmed] PHST- 2017/08/15 06:00 [medline] PHST- 2017/04/14 06:00 [entrez] AID - CS20170052 [pii] AID - 10.1042/CS20170052 [doi] PST - epublish SO - Clin Sci (Lond). 2017 May 22;131(11):1161-1178. doi: 10.1042/CS20170052. Print 2017 Jun 1.