Diallyl trisulfide exerts cardioprotection against myocardial ischemia-reperfusion injury in diabetic state, role of AMPK-mediated AKT/GSK-3β/HIF-1α activation

// Liming Yu 1, * , Wencheng Di 2, * , Xue Dong 3, 4, * , Zhi Li 1 , Xiaodong Xue 1 , Jian Zhang 1 , Qi Wang 1, 5 , Xiong Xiao 1, 6 , Jinsong Han 1 , Yang Yang 7, 8 and Huishan Wang 1 1 Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning 110016, China 2 Department of Cardiology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China 3 Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning 110016, China 4 Department of Neurosurgery, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning 110016, China 5 Graduate School, Dalian Medical University, Dalian, Liaoning 116044, China 6 Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China 7 Faculty of Life Science, Northwest University, Xi’an, Shaanxi 710069, China 8 Department of Biomedical Engineering, The Fourth Military Medical University, Xi’an, Shaanxi 710032, China * These authors have contributed equally to this work Correspondence to: Huishan Wang, email: huishanw@126.com Yang Yang, email: yang200214yy@163.com 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 ABSTRACT 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.