Cao Zhuoxiao, Hardej Diane, Trombetta Louis D, Trush Michael A, Li Yunbo
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Jamaica, NY 11439, USA.
Atherosclerosis. 2003 Feb;166(2):291-301. doi: 10.1016/s0021-9150(02)00331-3.
There is increasing evidence that aldehydes, including acrolein generated endogenously during the degradation process of biological molecules or the metabolism of foreign chemicals may be involved in the pathogenesis of cardiovascular diseases, such as atherosclerosis. Because glutathione (GSH) and GSH S-transferase (GST) are a major cellular defense against the toxic effects of reactive aldehydes, in this study we have characterized the inducibility of GSH and GST by the unique chemoprotective agent, 3H-1,2-dithiole-3-thione (D3T) and their protective effects against acrolein-induced toxicity in rat aortic smooth muscle A10 cells. Incubation of rat aortic A10 cells with micromolar concentrations of D3T resulted in a concentration- and time-dependent induction of both GSH and GST. Treatment of A10 cells with D3T also led to induction of gamma-glutamylcysteine synthetase, the key enzyme involved in GSH biosynthesis. Notably, the levels of GSH and GST remained higher than basal levels 72 h after removal of D3T from the culture media. To examine the protective effects of D3T-induced GSH and GST against reactive aldehyde-mediated toxicity, A10 cells were pretreated with D3T and then exposed to acrolein. Pretreatment of A10 cells with D3T resulted in a marked decrease of acrolein-induced toxicity as determined by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide reduction assay and morphological changes. To further demonstrate the involvement of GSH and GST in protecting against acrolein-induced toxicity, buthionine sulfoximine (BSO) and sulfasalazine were used to inhibit cellular GSH biosynthesis and GST activity, respectively. Either depletion of cellular GSH by BSO or inhibition of cellular GST by sulfasalazine led to a marked potentiation of acrolein-induced toxicity in A10 cells. Furthermore, co-treatment of cells with BSO was found to greatly abolish the protective effects of D3T on acrolein-induced toxicity. Taken together, our results demonstrate for the first time that both GSH and GST in aortic smooth muscle cells can be induced by D3T, and that this increased cellular defense affords great protection against reactive aldehyde-induced cardiovascular cell injury.
越来越多的证据表明，醛类物质，包括生物分子降解过程中内源性产生的丙烯醛或外来化学物质的代谢产物，可能参与心血管疾病如动脉粥样硬化的发病机制。由于谷胱甘肽（GSH）和谷胱甘肽S-转移酶（GST）是细胞抵御活性醛类毒性作用的主要防线，在本研究中，我们表征了独特的化学保护剂3H-1,2-二硫杂环戊烯-3-硫酮（D3T）对GSH和GST的诱导能力，以及它们对丙烯醛诱导的大鼠主动脉平滑肌A10细胞毒性的保护作用。用微摩尔浓度的D3T孵育大鼠主动脉A10细胞，会导致GSH和GST呈浓度和时间依赖性诱导。用D3T处理A10细胞还会导致γ-谷氨酰半胱氨酸合成酶的诱导，该酶是GSH生物合成中的关键酶。值得注意的是，从培养基中去除D3T 72小时后，GSH和GST的水平仍高于基础水平。为了研究D3T诱导的GSH和GST对活性醛介导的毒性的保护作用，A10细胞先用D3T预处理，然后暴露于丙烯醛。用D3T预处理A10细胞导致丙烯醛诱导的毒性显著降低，这通过3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四氮唑溴盐还原试验和形态学变化来确定。为了进一步证明GSH和GST参与抵御丙烯醛诱导的毒性，分别使用丁硫氨酸亚砜胺（BSO）和柳氮磺胺吡啶抑制细胞GSH生物合成和GST活性。用BSO耗尽细胞内的GSH或用柳氮磺胺吡啶抑制细胞内的GST都会导致A10细胞中丙烯醛诱导的毒性显著增强。此外，发现用BSO共同处理细胞会大大消除D3T对丙烯醛诱导毒性的保护作用。综上所述，我们的结果首次证明主动脉平滑肌细胞中的GSH和GST均可被D3T诱导，并且这种增强的细胞防御对活性醛诱导的心血管细胞损伤提供了强大的保护作用。
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