Inhibition of apoptotic signalling in spermine‐treated vascular smooth muscle cells by a novel glutathione precursor |
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Authors: | Indrani Sinha‐Hikim Ruoqing Shen Ekaterina Kovacheva Albert Crum Nosratola D Vaziri Keith C Norris |
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Institution: | 1. Department of Medicine, Charles Drew University, Los Angeles, CA 90059, U.S.A.;2. David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, U.S.A.;3. Proimmune, Rhinebeck, NY 12572, U.S.A.;4. Division of Nephrology and Hypertension, University of California, Irvine, CA 926974800, U.S.A. |
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Abstract: | 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‐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 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. |
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Keywords: | antioxidants apoptosis chronic kidney disease spermine vascular smooth muscle cells |
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