Abstract
During systemic inflammation, indoleamine 2,3-dioxygenase 1 (IDO1) becomes expressed in endothelial cells where it uses hydrogen peroxide (H2O2) to oxidize L-tryptophan to the tricyclic hydroperoxide, cis-WOOH, that then relaxes arteries via oxidation of protein kinase G 1α. Here we show that arterial glutathione peroxidases and peroxiredoxins that rapidly eliminate H2O2, have little impact on relaxation of IDO1-expressing arteries, and that purified IDO1 forms cis-WOOH in the presence of peroxiredoxin 2. cis-WOOH oxidizes protein thiols in a selective and stereospecific manner. Compared with its epimer trans-WOOH and H2O2, cis-WOOH reacts slower with the major arterial forms of glutathione peroxidases and peroxiredoxins while it reacts more readily with its target, protein kinase G 1α. Our results indicate a paradigm of redox signaling by H2O2 via its enzymatic conversion to an amino acid-derived hydroperoxide that ‘escapes’ effective reductive inactivation to engage in selective oxidative activation of key target proteins.
Highlights
During systemic inflammation, indoleamine 2,3-dioxygenase 1 (IDO1) becomes expressed in endothelial cells where it uses hydrogen peroxide (H2O2) to oxidize L-tryptophan to the tricyclic hydroperoxide, cis-WOOH, that relaxes arteries via oxidation of protein kinase G 1α
Depletion of thioredoxin and TrxR1 by small inhibitory RNA enhanced protein kinase G 1α (PKG1α) dimerization and relaxation of bovine pulmonary arteries in the presence of H2O224. These results suggest that Prx/glutathione peroxidases (GPx) regulate arterial redox signaling by H2O2 the impact of inflammation, when endogenous H2O2 is utilized to form cis-WOOH, on this process remains unclear
We hypothesized that H2O2 may act in a similar manner opposing noradrenaline-induced constriction (Fig. 1b), and that such effects are subject to regulation by Prx and GPx that metabolize H2O2 (Fig. 1c)
Summary
Indoleamine 2,3-dioxygenase 1 (IDO1) becomes expressed in endothelial cells where it uses hydrogen peroxide (H2O2) to oxidize L-tryptophan to the tricyclic hydroperoxide, cis-WOOH, that relaxes arteries via oxidation of protein kinase G 1α. While oxidation of L-Trp by reagent singlet oxygen or myeloperoxidase plus H2O2 gives rise to similar ratio of cis- and trans-WOOH, only cisWOOH is formed by IDO1 plus H2O29 These findings highlight the role of cis-WOOH as a stereoselective redox signaling molecule in arteries in inflammation. The two major thiol-containing reducing systems for the removal of hydroperoxides and maintenance of cellular protein thiol redox state are linked to thioredoxin and glutathione (GSH) The former is composed of Prx, thioredoxin, and thioredoxin reductase (TrxR), while the GSH reducing system consists of GPx, GSH, and glutathione reductase (GR)[11,12]. Depletion of thioredoxin and TrxR1 by small inhibitory RNA enhanced PKG1α dimerization and relaxation of bovine pulmonary arteries in the presence of H2O224 These results suggest that Prx/GPx regulate arterial redox signaling by H2O2 the impact of inflammation, when endogenous H2O2 is utilized to form cis-WOOH, on this process remains unclear
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