Background: Hyperglycemia-induced reactive oxygen species (ROS) generation contributes to development of diabetic cardiomyopathy. Nuclear factor E2-related factor 2 (Nrf2), a redox-sensing transcription factor, induces the antioxidant enzyme expressions. Diallyl trisulfide (DATS) is the most powerful antioxidant among the sulfur-containing compounds in garlic oil. We investigated whether DATS inhibits hyperglycemia-induced ROS production via Nrf2-mediated activation of antioxidant enzymes in cardiac cells exposed to high glucose (HG).
Methods and results: Treatment of H9c2 cells with HG resulted in an increase in intracellular ROS level and caspase-3 activity, which were markedly reduced by the administration of DATS (10 μM). DATS treatment significantly increased Nrf2 protein stability and nuclear translocation, upregulated downstream gene HO-1, and suppressed its repressor Keap1. However, apoptosis was not inhibited by DATS in cells transfected with Nrf2-specific siRNA. Inhibition of PI3K/Akt signaling by LY294002 (PI3K inhibitor) or PI3K-specific siRNA not only decreased the level of DATS-induced Nrf2-mediated HO-1 expression, but also diminished the protective effects of DATS. Similar results were also observed in high glucose-exposed neonatal primary cardiomyocytes and streptozotocin-treated diabetic rats fed DATS at a dose of 40 mg/kg BW.
Conclusions: Our findings indicate that DATS protects against hyperglycemia-induced ROS-mediated apoptosis by upregulating the PI3K/Akt/Nrf2 pathway, which further activates Nrf2-regulated antioxidant enzymes in cardiomyocytes exposed to HG.
Keywords: 2′,7′-dichlorofluorescein diacetate; Apo; Apoptosis; BW; DADS; DAS; DATS; DCF; DCFH-DA; DHE; DTT; Diallyl trisulfide (DATS); GSK3β; HG; HO-1; Hyperglycemia; Keap1; NG; Nrf2; Nuclear factor E2-related factor 2 (Nrf2); OSCs; ROS; Reactive oxygen species (ROS); SAPKs; SOD; STZ; TBARS; TUNEL; TXN-1; apocynin; body weight; dially trisulfide; diallyl disulfide; diallyl sulfide; dichlorofluorescein; dihydroethidium; dithiothreitol; glycogen synthase kinase 3β; heme oxygenase 1; high glucose; kelch-like ECH-associated protein 1; normal glucose; nuclear factor erythroid 2-related factor 2; organosulfur compounds; reactive oxygen species; streptozotocin; stress-activated protein kinases; superoxide dismutases; terminal deoxynucleotide transferase-mediated dUTP Nick End Labeling; thiobarbituric acid reactive substances; thioredoxin-1; γ-glutamylcysteine synthetase; γGCS.
Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.