Abstract
Carbon monoxide (CO) and nitric oxide (NO) each have mechanistically unique roles in various inflammatory disorders. Although it is known that CO can induce production of NO and that NO can induce expression of the cytoprotective enzyme heme oxygenase 1 (HO-1), there is no information whether the protective effect of CO ever requires NO production or whether either gas must induce expression of HO-1 to exert its functional effects. Using in vitro and in vivo models of tumor necrosis factor α–induced hepatocyte cell death in mice, we find that activation of nuclear factor κB and increased expression of inducible NO are required for the protective effects of CO, whereas the protective effects of NO require up-regulation of HO-1 expression. When protection from cell death is initiated by CO, NO production and HO-1 activity are each required for the protective effect showing for the first time an essential synergy between these two molecules in tandem providing potent cytoprotection.
Highlights
Inflammation and stress result in the induction of “protective genes” such as the inducible forms of heme oxygenase 1 (HO-1) and nitric oxide (NO) synthase II that generate the gaseous molecules carbon monoxide (CO) and NO, respectively
Our findings demonstrate a system of interdependence: exogenous CO protects through a nuclear factor (NF)-B–mediated, inducible nitric oxide synthase (iNOS)-dependent mechanism with NO subsequently protecting, at least in part, through an HO-1– dependent mechanism
Based on the protection conferred by HO-1 in vivo, we asked if exogenous CO would protect against hepatocyte cell death in vitro
Summary
Inflammation and stress result in the induction of “protective genes” such as the inducible forms of heme oxygenase 1 (HO-1) and nitric oxide (NO) synthase II (inducible NO synthase [iNOS]) that generate the gaseous molecules carbon monoxide (CO) and NO, respectively. Both HO-1 and iNOS are cytoprotective enzymes and when expressed produce therapeutic benefits in a number of conditions/ diseases. Recent findings suggest that one mechanism by which HO-1 protects is via generation of CO after the degradation of heme by HO-1 [8, 9] These two gases are linked in that NO can up-regulate HO-1 expression leading to the formation of endogenous
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