Diallyl trisulfide exerts cardioprotection against myocardial ischemia-reperfusion injury in diabetic state, role of AMPK-mediated AKT/GSK-3β/HIF-1α activation
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Liming Yu1,*, Wencheng Di2,*, Xue Dong3,4,*, Zhi Li1, Xiaodong Xue1, Jian Zhang1, Qi Wang1,5, Xiong Xiao1,6, Jinsong Han1, Yang Yang7,8 and Huishan Wang1
1Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning 110016, China
2Department of Cardiology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China
3Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning 110016, China
4Department of Neurosurgery, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning 110016, China
5Graduate School, Dalian Medical University, Dalian, Liaoning 116044, China
6Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China
7Faculty of Life Science, Northwest University, Xi’an, Shaanxi 710069, China
8Department of Biomedical Engineering, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China
*These authors have contributed equally to this work
Huishan Wang, email: [email protected]
Yang Yang, email: [email protected]
Keywords: diallyl trisulfide, diabetes mellitus, myocardial ischemia-reperfusion injury, AMPK, AKT/GSK-3β/HIF-1α signaling
Received: April 11, 2017 Accepted: June 28, 2017 Published: August 24, 2017
Diallyl trisulfide (DATS), the major active ingredient in garlic, has been reported to confer cardioprotective effects. However, its effect on myocardial ischemia-reperfusion (MI/R) injury in diabetic state and the underlying mechanism are still unknown. We hypothesize that DATS reduces MI/R injury in diabetic state via AMPK-mediated AKT/GSK-3β/HIF-1α activation. Streptozotocin-induced diabetic rats received MI/R surgery with or without DATS (20mg/kg) treatment in the presence or absence of Compound C (Com.C, an AMPK inhibitor, 0.25mg/kg) or LY294002 (a PI3K inhibitor, 5mg/kg). We found that DATS significantly improved heart function and reduced myocardial apoptosis. Additionally, in cultured H9c2 cells, DATS (10μM) also attenuated simulated ischemia-reperfusion injury. We found that AMPK and AKT/GSK-3β/HIF-1α signaling were down-regulated under diabetic condition, while DATS markedly increased the phosphorylation of AMPK, ACC, AKT and GSK-3β as well as HIF-1α expression in MI/R-injured myocardium. However, these protective actions were all blunted by Com.C administration. Additionally, LY294002 abolished the stimulatory effect of DATS on AKT/GSK-3β/HIF-1α signaling without affecting AMPK signaling. While 2-methoxyestradiol (a HIF-1α inhibitor) reduced HIF-1α expression without affecting AKT/GSK-3β signaling. Taken together, these data showed that DATS protected against MI/R injury in diabetic state by attenuating cellular apoptosis via AMPK-mediated AKT/GSK-3β/HIF-1α signaling. Its cardioprotective effect deserves further study.
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