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Inhibition of apoptotic signalling in spermine‐treated vascular smooth muscle cells by a novel glutathione precursor
Author(s) -
SinhaHikim Indrani,
Shen Ruoqing,
Kovacheva Ekaterina,
Crum Albert,
Vaziri Nosratola D.,
Norris Keith C.
Publication year - 2010
Publication title -
cell biology international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.932
H-Index - 77
eISSN - 1095-8355
pISSN - 1065-6995
DOI - 10.1042/cbi20090349
Subject(s) - spermine , apoptosis , cytochrome c , oxidative stress , glutathione , vascular smooth muscle , signal transduction , biology , biochemistry , chemistry , pharmacology , endocrinology , smooth muscle , enzyme
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 μM) with or without antioxidants (doses 50, 100, 200 and 500 μg/ml) were assessed for apoptosis, JNK (c‐Jun‐NH 2 ‐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 μg/ml) attenuated spermine‐induced acceleration of VSMC apoptosis but only F1 (at 200 and 500 μg/ml) maintained spermine‐induced apoptosis at control levels. Spermine‐induced JNK activation was prevented by 200 μg/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.