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Protecting against peroxynitrite-mediated cytotoxicity in vascular smooth muscle cells via upregulating endogenous glutathione biosynthesis by 3H-1,2-dithiole-3-thione

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Abstract

Peroxynitrite (ONOO−) is critically involved in the pathogenesis of cardiovascular diseases. Reaction with glutathione (GSH) was proposed to be a major detoxification pathway of ONOO− in the biological system. This study was undertaken to determine if chemically elevated intracellular GSH affords protection against ONOO−-mediated toxicity in vascular cells. Incubation of aortic smooth muscle A10 cells with 3H-1,2-dithiole-3-thione (D3T) led to a concentration- and time-dependent elevation of cellular GSH. Treatment of the cells with D3T also augmented protein and gene expression of γ-glutamylcysteine ligase. To examine the effects of D3T-induced GSH on ONOO−-mediated toxicity, we pretreated A10 cells with D3T and then exposed them to either authentic ONOO− or the ONOO− generator, 3-morpholinosydnonimine. We observed that D3T pretreatment of A10 cells resulted in a significant protection against ONOO− cytotoxicity. Conversely, depletion of cellular GSH by buthionine sulfoximine (BSO) caused a marked potentiation of ONOO− cytotoxicity. To further demonstrate the causal involvement of GSH induction in D3T cytoprotection, we cotreated A10 cells with BSO to abolish D3T-induced GSH elevation. BSO cotreatment was found to greatly reverse the protective effects of D3T on ONOO−-elicited cytotoxicity. Taken together, our results demonstrate that upregulating GSH biosynthesis by D3T results in a marked protection against ONOO−-induced toxicity in vascular cells.

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  1. Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Allied Health Professions, 8000 Utopia Parkway, 11439, Jamaica, NY

    Zhuoxiao Cao & Yunbo Li

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  1. Zhuoxiao Cao
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  2. Yunbo Li
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Correspondence to Yunbo Li.

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Cao, Z., Li, Y. Protecting against peroxynitrite-mediated cytotoxicity in vascular smooth muscle cells via upregulating endogenous glutathione biosynthesis by 3H-1,2-dithiole-3-thione. Cardiovasc Toxicol 4, 339–353 (2004). https://doi.org/10.1385/CT:4:4:339

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  • DOI: https://doi.org/10.1385/CT:4:4:339

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