Search

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] [...], 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.