Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation

Abstract

Singlet molecular oxygen (1O2) has well-established biological roles in plants, photosynthetic bacteria, some fungi, but not in mammals. We show here that 1O2 is formed by indoleamine 2,3-dioxygenase 1 in the vascular endothelium under inflammatory conditions and that this is associated with the stereo-selective oxidation of l-tryptophan to a tricyclic hydroperoxide via a previously unrecognized oxidative dioxygenase activity. The tryptophan-derived hydroperoxide then acts as a signaling molecule, inducing relaxation of arteries from different species and decreasing blood pressure in mice. This activity is dependent on a specific cysteine residue (cysteine-42) of protein kinase G1. Our findings indicate, for the first time, a (patho) physiological function for 1O2 in mammals via formation of a signaling molecule that regulates vascular tone and blood pressure during acute systemic inflammation.