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Antioxidant effects of diallyl trisulfide on high glucose-induced apoptosis are mediated by the PI3K/Akt-dependent activation of Nrf2 in cardiomyocytes.
Int J Cardiol. 2013 Sep 30; 168(2):1286-97.IJ

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.

Authors+Show Affiliations

Department of Pediatrics, China Medical University Beigang Hospital, Yunlin, Taiwan, ROC; Department of Biological Science & Technology College of Life Sciences, China Medical University, Taichung, Taiwan, ROC.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23453443

Citation

Tsai, Cheng-Yen, et al. "Antioxidant Effects of Diallyl Trisulfide On High Glucose-induced Apoptosis Are Mediated By the PI3K/Akt-dependent Activation of Nrf2 in Cardiomyocytes." International Journal of Cardiology, vol. 168, no. 2, 2013, pp. 1286-97.
Tsai CY, Wang CC, Lai TY, et al. Antioxidant effects of diallyl trisulfide on high glucose-induced apoptosis are mediated by the PI3K/Akt-dependent activation of Nrf2 in cardiomyocytes. Int J Cardiol. 2013;168(2):1286-97.
Tsai, C. Y., Wang, C. C., Lai, T. Y., Tsu, H. N., Wang, C. H., Liang, H. Y., & Kuo, W. W. (2013). Antioxidant effects of diallyl trisulfide on high glucose-induced apoptosis are mediated by the PI3K/Akt-dependent activation of Nrf2 in cardiomyocytes. International Journal of Cardiology, 168(2), 1286-97. https://doi.org/10.1016/j.ijcard.2012.12.004
Tsai CY, et al. Antioxidant Effects of Diallyl Trisulfide On High Glucose-induced Apoptosis Are Mediated By the PI3K/Akt-dependent Activation of Nrf2 in Cardiomyocytes. Int J Cardiol. 2013 Sep 30;168(2):1286-97. PubMed PMID: 23453443.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antioxidant effects of diallyl trisulfide on high glucose-induced apoptosis are mediated by the PI3K/Akt-dependent activation of Nrf2 in cardiomyocytes. AU - Tsai,Cheng-Yen, AU - Wang,Chien-Chung, AU - Lai,Tung-Yuan, AU - Tsu,Han-Nien, AU - Wang,Chung-Hsing, AU - Liang,Hsin-Yueh, AU - Kuo,Wei-Wen, Y1 - 2013/02/27/ PY - 2012/05/30/received PY - 2012/11/10/revised PY - 2012/12/01/accepted PY - 2013/3/5/entrez PY - 2013/3/5/pubmed PY - 2014/5/31/medline KW - 2′,7′-dichlorofluorescein diacetate KW - Apo KW - Apoptosis KW - BW KW - DADS KW - DAS KW - DATS KW - DCF KW - DCFH-DA KW - DHE KW - DTT KW - Diallyl trisulfide (DATS) KW - GSK3β KW - HG KW - HO-1 KW - Hyperglycemia KW - Keap1 KW - NG KW - Nrf2 KW - Nuclear factor E2-related factor 2 (Nrf2) KW - OSCs KW - ROS KW - Reactive oxygen species (ROS) KW - SAPKs KW - SOD KW - STZ KW - TBARS KW - TUNEL KW - TXN-1 KW - apocynin KW - body weight KW - dially trisulfide KW - diallyl disulfide KW - diallyl sulfide KW - dichlorofluorescein KW - dihydroethidium KW - dithiothreitol KW - glycogen synthase kinase 3β KW - heme oxygenase 1 KW - high glucose KW - kelch-like ECH-associated protein 1 KW - normal glucose KW - nuclear factor erythroid 2-related factor 2 KW - organosulfur compounds KW - reactive oxygen species KW - streptozotocin KW - stress-activated protein kinases KW - superoxide dismutases KW - terminal deoxynucleotide transferase-mediated dUTP Nick End Labeling KW - thiobarbituric acid reactive substances KW - thioredoxin-1 KW - γ-glutamylcysteine synthetase KW - γGCS SP - 1286 EP - 97 JF - International journal of cardiology JO - Int. J. Cardiol. VL - 168 IS - 2 N2 - 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. SN - 1874-1754 UR - https://www.unboundmedicine.com/medline/citation/23453443/Antioxidant_effects_of_diallyl_trisulfide_on_high_glucose_induced_apoptosis_are_mediated_by_the_PI3K/Akt_dependent_activation_of_Nrf2_in_cardiomyocytes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0167-5273(12)01632-4 DB - PRIME DP - Unbound Medicine ER -