Light in the dark – a novel path for the regulation of vascular tone

Indoleamine 2,3-dioxygenase 1 (IDO1) is a hem N-formyl-kynurenine (NFK), which is then converted to kynurenine and other biologically active metabolites. IDO1 shares numerous biological activities with nitric oxide synthase, including the regulation of vascular tone and blood pressure in conditions of inflammation (Nat Med 16:279) that are associated with elevated hydrogen peroxide (H2O2). We now report that in the presence of H2O2, recombinant human IDO1 generates singlet molecular oxygen, O2 (1Δg). This is associated with the stereospecific conversion of W to a tricyclic hydroperoxide (referred to as cis WOOH) that decays to NFK. IDO1/H2O2 generate cis WOOH via an oxidative dioxygenase reaction distinct from the presently known reductive dioxygenase and peroxidase activities of IDO1. cis WOOH, but not its stereoisomer trans WOOH, relaxes conduit arteries and resistance arterioles in mice and rats in a dose-dependent manner. Mechanistic studies indicate that arterial relaxation by cis WOOH is indepdent of soluble guanlyate cyclase, whereas it is attenuated by inhibitors of protein kinase G (PKG) and A, high potassium solution, and blockers to certain ion channels. Treatment of recombinant PKG1α and arterial segments cis WOOH causes dimerization of the protein, a process known to activate the kinase. Dimerization is not observed with C42S mutant PKG1α and it is more pronounced with cis WOOH than trans WOOH. Moreover, relaxation induced by cis WOOH is attenuated significantly in mesenteric arterioles from redox dead PKG1α-C42S knock-in compared with wild-type mice. Our results indicate that IDO1/H2O2 generate light in a dark reaction via formation of O2 (1Δg) that oxidizes W to the novel relaxant cis WOOH. Our studies also identify a novel pathway by which endothelial IDO1 may contribute to arterial relaxation and hypotension in inflammatory conditions such as those activated during severe sepsis.

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