Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation

Singlet molecular oxygen (¹O₂) has well-established roles in photosynthetic plants, bacteria and fungi^1-3, but not in mammals. Chemically generated ¹O₂ oxidizes the amino acid tryptophan to precursors of a key metabolite called N-formylkynurenine⁴, whereas enzymatic oxidation of tryptophan to N-formylkynurenine is catalysed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 1⁵. Under inflammatory conditions, this haem-containing enzyme is expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure⁶. However, whether indoleamine 2,3-dioxygenase 1 forms ¹O₂ 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 ¹O₂. We observed that in the presence of hydrogen peroxide, the enzyme generates ¹O₂ 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 G1α. Our findings demonstrate a pathophysiological role for ¹O₂ in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions.