Genetic responses against nitric oxide toxicity

Abstract

The threat of free radical damage is opposed by coordinated responses that modulate expression of sets of gene products. In mammalian cells, 12 proteins are induced by exposure to nitric oxide (NO) levels that are sub-toxic but exceed the level needed to activate guanylate cyclase. Heme oxygenase 1 (HO-1) synthesis increases substantially, due to a 30-to 70-fold increase in the level of HO-1 mRNA. HO-1 induction is cGMP-independent and occurs mainly through increased mRNA stability, which therefore indicates a new NO-signaling pathway. HO-1 induction contributes to dramatically increased NO resistance and, together with the other inducible functions, constitutes an adaptive resistance pathway that also defends against oxidants such as H 2 O 2 . In E. coli, an oxidative stress response, the soxRS regulon, is activated by direct exposure of E. coli to NO, or by NO generated in murine macrophages after phagocytosis of the bacteria. This response is governed by the SoxR protein, a homodimeric transcription factor (17-kDa subunits) containing [2Fe-2S] clusters essential for its activity. SoxR responds to superoxide stress through one-electron oxidation of the iron-sulfur centers, but such oxidation is not observed in reactions of NO with SoxR. Instead, NO nitrosylates the iron-sulfur centers of SoxR both in vitro and in intact cells, which yields a form of the protein with maximal transcriptional activity. Although nitrosylated SoxR is very stable in purified form, the spectroscopic signals for the nitrosylated iron-sulfur centers disappear rapidly in vivo, indicating an active process to reverse or eliminate them.

Expression and subcellular localization of BNIP3 in hypoxic hepatocytes and liver stress

“…For over 15 years, it has been recognized that NO participates in the regulation of gene expression (12,28,29). Confirming our hypothesis that the antiapoptotic effects of NO in hepatocytes (18) may also be mediated by modulation of gene expression, we found induction of the antiapoptotic genes BAG-1 and heat shock protein 70 and reduction of the proapoptotic genes sox-4, calpain, R-ras gene, interleukin-1␤-converting enzyme-like cysteine protease (Lice) gene, and RIP gene by iNOS in mouse hepatocytes (54).…”

Continuous Administration of Organic Nitrate Decreases Hepatic Cytochrome P450

“…NO is a well known inducer of HO-1 mRNA (Hartsfield et al, 1997;Demple, 1999;Bouton and Demple, 2000), and HO-1 has been shown to suppress the levels of P450 proteins in a tissue-specific manner with concomitant effects on their activity (Botros et al, 2002). Furthermore, HO-1 induction was reported to decrease various isoforms of P450 enzymes (Da Silva et al, 1994;Iba et al, 1999;Kobayashi et al, 2000).…”

“…This process is P450-dependent (McGuire et al, 1998), and huge amounts of NO are produced via the degradation of organic nitrate. NO directly and indirectly inactivates and degrades P450 (Khat-senko et al, 1993;Shiro et al, 1995;Snyder et al, 1996;Minamiyama et al, 1997a;Demple, 1999;Takemura et al, 1999). Therefore, hepatic P450 may be inactivated along with the NO production pathway of organic nitrates.…”

NO-mediated cytoprotection: Instant adaptation to oxidative stress in bacteria

“…Several bacterial proteins have been shown to change their properties upon interaction with NO. For example, the transcription factors OxyR, SoxR, NorR, and Fur (5)(6)(7) in Escherichia coli and ResDE in Bacillus subtilis (8) activate corresponding regulons upon reaction with NO. Furthermore, several Gram-positive bacteria, including B. subtilis, possess an enzyme orthologous to eukaryotic NOS (9)(10)(11)(12)(13).…”

“…In mammals, NO͞SNO influence ranges from cytoprotection to cytotoxicity (5,(15)(16)(17). NO has been shown to protect various types of eukaryotic cells from H 2 O 2 and organic peroxide-mediated toxicity (18)(19)(20)(21)(22)(23)(24), although the molecular mechanism of NO mediated cytoprotection has not been elucidated.…”