Department of Medicine, Charles Drew University, Los Angeles, CA 90059, USA.
Cell Biol Int. 2010 Apr 1;34(5):503-11. doi: 10.1042/CBI20090349.
CKD (chronic kidney disease) is a public health problem, mediated by haemodynamic and non-haemodynamic events including oxidative stress. We investigated the effect of two GSH (glutathione) precursors, NAC (N-acetylcysteine) and cystine as the physiological carrier of cysteine in GSH with added selenomethionine (F1) in preventing spermine (uraemic toxin)-induced apoptosis in cultured human aortic VSMC (vascular smooth muscle cells). VSMCs exposed to spermine (15 microM) with or without antioxidants (doses 50, 100, 200 and 500 microg/ml) were assessed for apoptosis, JNK (c-Jun-NH2-terminal kinase) activation and iNOS (inducible nitric oxide synthase) induction and activation of intrinsic pathway signalling. Spermine exposure resulted in activation of JNK and iNOS induction and apoptosis. NAC and F1 (dose range 50-500 microg/ml) attenuated spermine-induced acceleration of VSMC apoptosis but only F1 (at 200 and 500 microg/ml) maintained spermine-induced apoptosis at control levels. Spermine-induced JNK activation was prevented by 200 microg/ml of both NAC and F1, while iNOS induction was blocked only by F1. Notably, the adverse effects of spermine on BAX/BCL-2 ratio, cytochrome c release and caspase activation was fully attenuated by F1. In conclusion, F1 was more effective than NAC in preventing spermine-induced apoptosis and downstream changes in related signal transduction pathways in VSMCs. Further studies are needed to examine the effect of these compounds in preventing CKD-associated vascular disease.
慢性肾脏病（CKD）是一个公共健康问题，由包括氧化应激在内的血流动力学和非血流动力学事件介导。我们研究了两种谷胱甘肽（GSH）前体 N-乙酰半胱氨酸（NAC）和胱氨酸的生理载体胱氨酸二肽（作为 GSH 的载体并添加硒代蛋氨酸（F1））在预防精脒（尿毒症毒素）诱导的培养人主动脉血管平滑肌细胞（VSMC）凋亡中的作用。用或不用抗氧化剂（剂量为 50、100、200 和 500μg/ml）将暴露于精脒（15μM）的 VSMC 评估凋亡、JNK（c-Jun-NH2-末端激酶）激活和 iNOS（诱导型一氧化氮合酶）诱导以及内在途径信号转导的激活。精脒暴露导致 JNK 激活和 iNOS 诱导和凋亡加速。NAC 和 F1（剂量范围 50-500μg/ml）减弱了精脒诱导的 VSMC 凋亡加速，但只有 F1（在 200 和 500μg/ml）将精脒诱导的凋亡维持在对照水平。200μg/ml 的 NAC 和 F1 均可预防精脒诱导的 JNK 激活，而只有 F1 可阻止 iNOS 诱导。值得注意的是，F1 完全减弱了精脒对 BAX/BCL-2 比、细胞色素 c 释放和半胱天冬酶激活的不良影响。总之，F1 比 NAC 更有效地预防 VSMC 中精脒诱导的凋亡和下游相关信号转导途径的改变。需要进一步研究这些化合物在预防 CKD 相关血管疾病中的作用。
