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Singlet molecular oxygen (.sup.1O.sub.2) has well-established roles in photosynthetic plants, bacteria and fungi.sup.1-3, but not in mammals. Chemically generated .sup.1O.sub.2 oxidizes the amino acid tryptophan to precursors of a key metabolite called N-formylkynurenine.sup.4, whereas enzymatic oxidation of tryptophan to N-formylkynurenine is catalysed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 1.sup.5. Under inflammatory conditions, this haem-containing enzyme is expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure.sup.6. However, whether indoleamine 2,3-dioxygenase 1 forms .sup.1O.sub.2 and whether this contributes to blood pressure control have remained unknown. Here we show that arterial indoleamine 2,3-dioxygenase 1 regulates blood pressure via formation of .sup.1O.sub.2. We observed that in the presence of hydrogen peroxide, the enzyme generates .sup.1O.sub.2 and that this is associated with the stereoselective oxidation of l-tryptophan to a tricyclic hydroperoxide via a previously unrecognized oxidative activation of the dioxygenase activity. The tryptophan-derived hydroperoxide acts in vivo as a signalling molecule, inducing arterial relaxation and decreasing blood pressure; this activity is dependent on Cys42 of protein kinase G1[alpha]. Our findings demonstrate a pathophysiological role for .sup.1O.sub.2 in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions. Singlet molecular oxygen, produced by indoleamine 2,3-dioxygenase 1 activity, gives rise to a signalling molecule that regulates arterial relaxation under inflammatory conditions., Author(s): Christopher P. Stanley [sup.1] , Ghassan J. Maghzal [sup.1] [sup.2] , Anita Ayer [sup.1] [sup.2] , Jihan Talib [sup.1] [sup.2] , Andrew M. Giltrap [sup.3] , Sudhir Shengule [sup.1] [...]

Chroni→c granulomatous disease (CGD) is an inherited disorder of phagocyte function, caused by a genetic defect in NADPH oxidase (NOX2), leading to an impaired ability of leukocytes to produce superoxide [...]

Indoleamine 2,3-dioxygenase-1 (IDO1) mediates the degradation of L-tryptophan (L-Trp) and is constitutively expressed in the chorionic vascular endothelium of the human placenta with highest levels in the microvasculature. Given that endothelial expression of IDO1 has been shown to regulate vascular tone and blood pressure in mice under the condition of systemic inflammation, we asked whether IDO1 is also involved in the regulation of placental blood flow and if yes, whether this function is potentially impaired in intrauterine growth restriction (IUGR) and pre-eclampsia (PE). In the large arteries of the chorionic plate L-Trp induced relaxation only after upregulation of IDO1 using interferon gamma and tumor necrosis factor alpha. However, ex vivo placental perfusion of pre-constricted cotyledonic vasculature with L-Trp decreases the vessel back pressure without prior IDO1 induction. Further to this finding, IDO1 protein expression and activity is reduced in IUGR and PE when compared to gestational age-matched control tissue. These data suggest that L-Trp catabolism plays a role in the regulation of placental vascular tone, a finding which is potentially linked to placental and fetal growth. In this context our data suggest that IDO1 deficiency is related to the pathogenesis of IUGR and PE.