Antioxidant effects of diallyl trisulfide on high glucose-induced apoptosis are mediated by the PI3K/Akt-dependent activation of Nrf2 in cardiomyocytes

Cheng Yen Tsai, Chien Chung Wang, Tung-Iuan Lai, Han Nien Tsu, Chung Hsing Wang, Hsin Yueh Liang, Wei Wen Kuo

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87 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1286-1297
Number of pages12
JournalInternational Journal of Cardiology
Volume168
Issue number2
DOIs
Publication statusPublished - Sep 30 2013

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Keywords

  • Apoptosis
  • Diallyl trisulfide (DATS)
  • Hyperglycemia
  • Nuclear factor E2-related factor 2 (Nrf2)
  • Reactive oxygen species (ROS)

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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