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

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.

Cardioprotective effect of garlic extract in isoproterenol-induced myocardial infarction in a rat model: assessment of pro-apoptotic caspase-3 gene expression

“…This confirms that GE has the potentiality of Casp3 gene down regulation. It has also been reported that active ingredients like s-allyl-cysteine sulfoxide (alliin) [14], diallyl trisulfide (DATS) [15] decreased Casp3 and protects the heart against ischemia/reperfusion injury in rats by inhibiting apoptosis. So inhibiting the expression of apoptotic Casp3 gene by GE treatment may reduce the risk of myocardial infarction.…”

“…Garlic (Allium sativum), a spice belongs to the Alliacae family, and its preparations have been widely recognized as agents for prevention and treatment of CVDs like atherosclerosis, hyperlipidemia, thrombosis, and hypertension [13]. Recent molecular studies have also demonstrated that active ingredients like s-allyl-cysteine sulfoxide (alliin) [14], diallyl trisulfide (DATS) [15], Allicin (2-propene-1-sulfinothioic acid S-2-propenyl ester, diallyl thiosulfinate) [16,17] of garlic protect cardiac tissue through down regulating the expression of some CVD causing apoptotic genes.…”

The impacts of garlic and voluntary training alone or together on myocardial miR-126 and miR-210 gene expressions and angiogenesis in healthy rats

“…Moreover, it was demonstrated that garlic usage in the diet is strongly associated with cardiovascular injury and ischemic insult. Cardioprotective effect of garlic has been attributed to the antioxidant activities, 19 AMPK-regulated AKT/GSK-3β/HIF-1α pathway, 32 and Akt-eNOS signaling pathways. 33 However, it’s fully mechanisms is still in debate.…”

“…Also, garlic protects the heart in ischemia-reperfusion injury in part by HIF-1α activation. 32 Therefore, considering the above information, garlic can up-regulate the expression of miR-210 in the myocardium resulted in the angiogenesis process mediated by HIF-1α activation.…”

Mechanisms underlying the attenuation of chronic inflammatory diseases by aged garlic extract: Involvement of the activation of AMP‑activated protein kinase (Review)

“…AGE has been shown to exert immunomodulatory effects (17)(18)(19)(20), anti-atherosclerotic effects (21)(22)(23)(24)(25), anti-hypertensive effects (26)(27)(28)(29), antioxidant effects (30)(31)(32) and blood flow-improving effects (33) in clinical and animal studies. In addition, recent studies have suggested that AGE and its components can induce the activation of AMPK in several cell types and tissues (19,23,(34)(35)(36)(37).…”