- Title
- Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation
- Creator
- Stanley, Christopher; Maghzal, Ghassan; Ayer, Anita; Talib, Jihan; Giltrap, Andrew; Shengule, Sudhir; Wolhuter, Kathryn; Wang, Yutang; Chadha, Preet; Suarna, Cacang; Prysyazhna, Oleksandra; Scotcher, Jenna; Dunn, Louise; Prado, Fernanda; Nguyen, Nghi; Odiba, Jephthah; Baell, Johathan; Stasch, Johannes-Peter; Yamamoto, Yorihiro; Di Mascio, Paolo; Eaton, Philip; Payne, Richard; Stocker, Roland
- Date
- 2019
- Type
- Text; Journal article; Letter
- Identifier
- http://researchonline.federation.edu.au/vital/access/HandleResolver/1959.17/169229
- Identifier
- vital:13999
- Identifier
-
https://doi.org/10.1038/s41586-019-0947-3
- Identifier
- ISBN:0028-0836
- Abstract
- Singlet molecular oxygen (O-1(2)) has well-established roles in photosynthetic plants, bacteria and fungi(1-3), but not in mammals. Chemically generated O-1(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 O-1(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 O-1(2). We observed that in the presence of hydrogen peroxide, the enzyme generates O-1(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 O-1(2) in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions.
- Publisher
- Nature Publishing Group
- Relation
- Nature Vol. 566, no. 7745 (2019), p. 548-552
- Rights
- Copyright © 2019, The Author(s), under exclusive licence to Springer Nature Limited.
- Rights
- Open Access
- Rights
- This metadata is freely available under a CCO license
- Subject
- MD Multidisciplinary; Singlet molecular oxygen; Vascular tone; Blood pressure; Inflammation
- Full Text
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