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 Mascio, Philip Eaton, Richard J. Payne and Roland Stocker ()
Additional contact information
Christopher P. Stanley: Victor Chang Cardiac Research Institute
Ghassan J. Maghzal: Victor Chang Cardiac Research Institute
Anita Ayer: Victor Chang Cardiac Research Institute
Jihan Talib: Victor Chang Cardiac Research Institute
Andrew M. Giltrap: The University of Sydney
Sudhir Shengule: Victor Chang Cardiac Research Institute
Kathryn Wolhuter: Victor Chang Cardiac Research Institute
Yutang Wang: The University of Sydney
Preet Chadha: Victor Chang Cardiac Research Institute
Cacang Suarna: Victor Chang Cardiac Research Institute
Oleksandra Prysyazhna: Cardiovascular Division, King’s College London
Jenna Scotcher: Cardiovascular Division, King’s College London
Louise L. Dunn: Victor Chang Cardiac Research Institute
Fernanda M. Prado: Universidade de São Paulo
Nghi Nguyen: Monash University
Jephthah O. Odiba: Monash University
Jonathan B. Baell: Monash University
Johannes-Peter Stasch: Cardiovascular Research, Bayer AG
Yorihiro Yamamoto: Tokyo University of Technology
Paolo Mascio: Universidade de São Paulo
Philip Eaton: Cardiovascular Division, King’s College London
Richard J. Payne: The University of Sydney
Roland Stocker: Victor Chang Cardiac Research Institute

Nature, 2019, vol. 566, issue 7745, 548-552

Abstract: Abstract Singlet molecular oxygen (1O2) has well-established roles in photosynthetic plants, bacteria and fungi1–3, 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.

Date: 2019
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DOI: 10.1038/s41586-019-0947-3

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