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

被引：18

作者：

Cao Z. ^{[1
]}

Li Y. ^{[1
,2
]}

机构：

[1] Dept. of Pharmaceutical Sciences, St. John's University, Coll. Pharm./All. Hlth. Professions, Jamaica, NY

[2] Dept. of Pharmaceutical Sciences, Coll. Pharm./All. Hlth. Professions, St. John's University, Jamaica, NY 11439

来源：

Cardiovascular Toxicology | 2004年 / 4卷 / 4期

基金：

美国国家卫生研究院;

关键词：

γ-glutamylcysteine ligase; 3H-1,2-dithiole-3-thione; Glutathione; Peroxynitrite; Smooth muscle cells;

D O I：

10.1385/CT:4:4:339

中图分类号：

学科分类号：

摘要：

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.

引用

页码：339 / 353

页数：14

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