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.
Highlights
Coronary artery disease (CAD) is a major cause of death and disability in developing countries
We found that AMP-activated protein kinase (AMPK) and AKT/ Glycogen synthase kinase-3β (GSK-3β)/Hypoxiainducible factor-1α (HIF-1α) signaling were down-regulated under diabetic condition, while Diallyl trisulfide (DATS) markedly increased the phosphorylation of AMPK, ACC, AKT and GSK-3β as well as HIF-1α expression in myocardial ischemiareperfusion (MI/R)-injured myocardium
In the present study, we firstly evaluated AMPK and AKT/GSK-3β/HIF-1α signaling in the left ventricular of diabetic and non-diabetic rats (Figure 2)
Summary
Coronary artery disease (CAD) is a major cause of death and disability in developing countries. Timely reperfusion (such as thrombolytic therapy) is the main treatment to limit infarct size and attenuate cardiac damage, reperfusion itself exacerbates myocardial injury and cellular death, commonly termed as ‘myocardial ischemia-reperfusion (MI/R) injury’ [1, 2]. Numerous basic and clinical studies revealed that diabetes mellitus (DM), a common chronic metabolic disease, dramatically increased the risk of CAD, followed by significantly increased cardiac damage and mortality risk [3]. During MI/R injury, cardiac damage is more dominant in reperfusion period than that in ischemia period and enhanced cellular apoptosis is deemed to be one of the main causes, especially in diabetic state [3, 4]. There is still a lack of safe and effective therapeutic strategy against diabetic MI/R injury
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