PMID- 28765969 OWN - NLM STAT- MEDLINE DCOM- 20180423 LR - 20211204 IS - 1791-3004 (Electronic) IS - 1791-2997 (Linking) VI - 16 IP - 3 DP - 2017 Sep TI - AMPK activation restores ischemic post‑conditioning cardioprotection in STZ‑induced type 1 diabetic rats: Role of autophagy. PG - 3648-3656 LID - 10.3892/mmr.2017.7033 [doi] AB - Although the mechanism remains unclear, ischemic post‑conditioning (IPO) is a promising approach to combat myocardial ischemia reperfusion (IR) injury; however, it has been proven ineffective in diabetes. The present study aimed to identify whether hyperglycemia‑induced AMP‑activated protein kinase (AMPK) inhibition contributes to the ineffectiveness of IPO via autophagy attenuation in diabetic hearts. Diabetic and non‑diabetic rats were subjected to myocardial IR and/or IPO with/without treatment with the AMPK activator A‑769662 and/or autophagy inhibitor 3‑methyladenine (3‑MA). Rat cardiomyocyte H9c2 cells were pretreated with A‑769662 and/or 3‑MA, and subjected to hypoxia reoxygenation (HR) or hypoxia post‑conditioning (HPO). The degree of injury to the myocardium/cells, oxidative stress, AMPK/mammalian target of rapamycin (mTOR) signaling and autophagy status were analyzed. In diabetic rats the myocardial infarct size, and creatine kinase‑MB and malondialdehyde release, were increased compared with non‑diabetic rats, concomitant with increased cardiac dysfunction and decreased cardiac superoxide dismutase activity, AMPK phosphorylation and autophagy following IR. IPO attenuated myocardial infarct size, increased AMPK phosphorylation and enhanced autophagy in non‑diabetic animals. A‑769662 (6.0 mg/kg) restored IPO cardioprotection in diabetic rats. In vitro, HPO combined with A‑769662 decreased HR injury in H9c2 cells exposed to high glucose, as evidenced by decreased lactic dehydrogenase expression and oxidative stress, accompanied by increased cell viability and autophagy. The A‑769662‑mediated restoration of IPO/HPO cardioprotection was completely reversed by treatment with the autophagy inhibitor 3‑MA. In conclusion, AMPK inhibition, by decreasing autophagy, may be a mechanism through which diabetic hearts are rendered unresponsive to IPO cardioprotection. FAU - Zhou, Bin AU - Zhou B AD - Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China. FAU - Leng, Yan AU - Leng Y AD - Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China. FAU - Lei, Shao-Qing AU - Lei SQ AD - Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China. FAU - Xia, Zhong-Yuan AU - Xia ZY AD - Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China. LA - eng PT - Journal Article DEP - 20170718 PL - Greece TA - Mol Med Rep JT - Molecular medicine reports JID - 101475259 RN - 0 (Biphenyl Compounds) RN - 0 (Pyrones) RN - 0 (Thiophenes) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - P68477CD2C (4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile) SB - IM MH - AMP-Activated Protein Kinases/antagonists & inhibitors/*metabolism MH - Animals MH - *Autophagy MH - Biphenyl Compounds MH - *Diabetes Mellitus, Experimental/enzymology/pathology/therapy MH - *Diabetes Mellitus, Type 1/enzymology/pathology/therapy MH - *Diabetic Cardiomyopathies/enzymology/pathology/prevention & control MH - Enzyme Activation/drug effects MH - *Ischemic Postconditioning MH - Male MH - Pyrones/pharmacology MH - Rats MH - Rats, Sprague-Dawley MH - Thiophenes/pharmacology EDAT- 2017/08/03 06:00 MHDA- 2018/04/24 06:00 CRDT- 2017/08/03 06:00 PHST- 2016/05/31 00:00 [received] PHST- 2017/04/07 00:00 [accepted] PHST- 2017/08/03 06:00 [pubmed] PHST- 2018/04/24 06:00 [medline] PHST- 2017/08/03 06:00 [entrez] AID - 10.3892/mmr.2017.7033 [doi] PST - ppublish SO - Mol Med Rep. 2017 Sep;16(3):3648-3656. doi: 10.3892/mmr.2017.7033. Epub 2017 Jul 18.