Nitric oxide fully protects against UVA-induced apoptosis in tight correlation with Bcl-2 up-regulation

被引:145
作者
Suschek, CV
Krischel, V
Bruch-Gerharz, D
Berendji, D
Krutmann, J
Kröncke, KD
Kolb-Bachofen, V
机构
[1] Univ Dusseldorf, Inst Immunobiol, Res Grp Immunobiol, D-40001 Dusseldorf, Germany
[2] Univ Dusseldorf, Dept Dermatol, D-40001 Dusseldorf, Germany
关键词
D O I
10.1074/jbc.274.10.6130
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A variety of toxic and modulating events induced by WA exposure are described to cause cell death via apoptosis, Recently, we found that UV irradiation of human skin leads to inducible nitric-oxide synthase (iNOS) expression in keratinocytes and endothelial cells (ECs). We have now searched for the role of MOS expression and nitric oxide (NO) synthesis in UVA-induced apoptosis as detected by DNA-specific fluorochrome labeling and in DNA fragmentation visualized by in situ nick translation in ECs, Activation with proinflammatory cytokines 24 h before WA exposure leading to iNOS expression and endogenous NO synthesis fully protects ECs from the onset of apoptosis. This protection was completely abolished in the presence of the iNOS inhibitor L-N-5-(1-iminoethyl)-ornithine (0.25 mM). Additionally, preincubation of cells with the NO donor (Z)-1-[N(2-aminoethyl) -N-(2-ammonioethyl)amino] diazen-1-ium-1,2-diolate at concentrations from 10 to 1000 mu M as an exogenous NO-generating source before UVA irradiation led to a dose-dependent inhibition of both DNA strand breaks and apoptosis, In search of the molecular mechanism responsible for the protective effect, we find that protection from UVA-induced apoptosis is tightly correlated with NO-mediated increases in Bcl-2 expression and a concomitant inhibition of WA-induced overexpression of Bar protein. In conclusion, we present evidence for a protective role of iNOS-derived NO in skin biology, because NO either endogenously produced or exogenously applied fully protects against WA-induced cell damage and death. me also show that the NO-mediated expression modulation of proteins of the Bcl-2 family, an event upstream of caspase activation, appears to be the molecular mechanism underlying this protection.
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页码:6130 / 6137
页数:8
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