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

Research output: Contribution to journalArticle

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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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NF-E2-Related Factor 2
Phosphatidylinositol 3-Kinases
Cardiac Myocytes
Antioxidants
Apoptosis
Glucose
Reactive Oxygen Species
Hyperglycemia
Small Interfering RNA
Diabetic Cardiomyopathies
diallyl trisulfide
Sulfur Compounds
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Enzyme Activation
Protein Stability
Enzymes
Streptozocin
Caspase 3
Oxidation-Reduction
Transcription Factors

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

Cite this

Antioxidant effects of diallyl trisulfide on high glucose-induced apoptosis are mediated by the PI3K/Akt-dependent activation of Nrf2 in cardiomyocytes. / Tsai, Cheng Yen; Wang, Chien Chung; Lai, Tung-Iuan; Tsu, Han Nien; Wang, Chung Hsing; Liang, Hsin Yueh; Kuo, Wei Wen.

In: International Journal of Cardiology, Vol. 168, No. 2, 30.09.2013, p. 1286-1297.

Research output: Contribution to journalArticle

Tsai, Cheng Yen ; Wang, Chien Chung ; Lai, Tung-Iuan ; Tsu, Han Nien ; Wang, Chung Hsing ; Liang, Hsin Yueh ; Kuo, Wei Wen. / Antioxidant effects of diallyl trisulfide on high glucose-induced apoptosis are mediated by the PI3K/Akt-dependent activation of Nrf2 in cardiomyocytes. In: International Journal of Cardiology. 2013 ; Vol. 168, No. 2. pp. 1286-1297.
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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.",
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AU - Lai, Tung-Iuan

AU - Tsu, Han Nien

AU - Wang, Chung Hsing

AU - Liang, Hsin Yueh

AU - Kuo, Wei Wen

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AB - 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.

KW - Apoptosis

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KW - Hyperglycemia

KW - Nuclear factor E2-related factor 2 (Nrf2)

KW - Reactive oxygen species (ROS)

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