Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation

Christopher P. Stanley, Ghassan J. Maghzal, Anita Ayer, Jihan Talib, Andrew M. Giltrap, Sudhir Shengule, Kathryn Wolhuter, Yutang Wang, Preet Chadha, Cacang Suarna, Oleksandra Prysyazhna, Jenna Scotcher, Louise L. Dunn, Fernanda M. Prado, Nghi Nguyen, Jephthah O. Odiba, Jonathan B. Baell, Johannes Peter Stasch, Yorihiro Yamamoto, Paolo Di MascioPhilip Eaton, Richard J. Payne, Roland Stocker

Research output: Contribution to journalLetterResearchpeer-review

32 Citations (Scopus)

Abstract

Singlet molecular oxygen ( 1 O 2 ) has well-established roles in photosynthetic plants, bacteria and fungi 1–3 , but not in mammals. Chemically generated 1 O 2 oxidizes the amino acid tryptophan to precursors of a key metabolite called N-formylkynurenine 4 , whereas enzymatic oxidation of tryptophan to N-formylkynurenine is catalysed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 1 5 . Under inflammatory conditions, this haem-containing enzyme is expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure 6 . However, whether indoleamine 2,3-dioxygenase 1 forms 1 O 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 1 O 2 . We observed that in the presence of hydrogen peroxide, the enzyme generates 1 O 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 G1α. Our findings demonstrate a pathophysiological role for 1 O 2 in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions.

Original languageEnglish
Pages (from-to)548-552
Number of pages5
JournalNature
Volume566
Issue number7745
DOIs
Publication statusPublished - 28 Feb 2019

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