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  • Title: Modification of macrophage glyceraldehyde-3-phosphate dehydrogenase in response to nitric oxide.
    Author: Messmer UK, Brüne B.
    Journal: Eur J Pharmacol; 1996 Apr 29; 302(1-3):171-82. PubMed ID: 8791005.
    Abstract:
    A potential cytotoxic, self-destructive role of endogenously generated and exogenously supplied nitric oxide (NO) was studied in two mouse monocytic macrophage cell lines (RAW 264.7 and J774.1). Our attention centered on NO-mediated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) modification and inhibition of the Krebs cycle enzyme, aconitase, related to macrophage cell death. NO formed by an active inducible nitric oxide synthase significantly decreased cell viability in the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cytotoxicity assay. Similarly, cell viability was inversely and dose-dependently correlated to increasing concentrations of the NO-releasing compound, sodium nitroprusside. Biochemically, we noticed a correlation between endogenously derived or exogenously generated NO and inhibition of GAPDH as well as aconitase enzyme activity. The involvement of NO was further substantiated by the use of NG-monomethyl-L-arginine. Associated with decreased GAPDH enzyme activity, 32P-NAD(+)-dependent modification of the enzyme in the cytosol of pretreated cells was hindered. This reflects intracellular protein modification as a result of NO signalling. Using sodium nitroprusside we achieved GAPDH translocation from the cytosol to the plasma membrane or the nucleus of treated cells. However, despite GAPDH modification, lactate production was not rate limiting during NO intoxication. Furthermore, blocking the iron-sulfur-containing enzyme, aconitase, is insufficient to produce macrophage cell death. Although RAW 264.7 and J774.1 cells show substantial variation in their sensitivity towards NO it can be concluded that NO-mediated macrophage cell death is not linked to energy depletion. For GAPDH, NO-mediated protein modification may be related to functions of the enzyme, other than its glycolytic role.
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