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 Mascio & 3 others Philip Eaton, Richard J. Payne, Roland Stocker

Research output: Contribution to journalLetterResearchpeer-review

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

Cite this

Stanley, C. P., Maghzal, G. J., Ayer, A., Talib, J., Giltrap, A. M., Shengule, S., ... Stocker, R. (2019). Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation. Nature, 566(7745), 548-552. https://doi.org/10.1038/s41586-019-0947-3
Stanley, Christopher P. ; Maghzal, Ghassan J. ; Ayer, Anita ; Talib, Jihan ; Giltrap, Andrew M. ; Shengule, Sudhir ; Wolhuter, Kathryn ; Wang, Yutang ; Chadha, Preet ; Suarna, Cacang ; Prysyazhna, Oleksandra ; Scotcher, Jenna ; Dunn, Louise L. ; Prado, Fernanda M. ; Nguyen, Nghi ; Odiba, Jephthah O. ; Baell, Jonathan B. ; Stasch, Johannes Peter ; Yamamoto, Yorihiro ; Di Mascio, Paolo ; Eaton, Philip ; Payne, Richard J. ; Stocker, Roland. / Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation. In: Nature. 2019 ; Vol. 566, No. 7745. pp. 548-552.
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title = "Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation",
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.",
author = "Stanley, {Christopher P.} and Maghzal, {Ghassan J.} and Anita Ayer and Jihan Talib and Giltrap, {Andrew M.} and Sudhir Shengule and Kathryn Wolhuter and Yutang Wang and Preet Chadha and Cacang Suarna and Oleksandra Prysyazhna and Jenna Scotcher and Dunn, {Louise L.} and Prado, {Fernanda M.} and Nghi Nguyen and Odiba, {Jephthah O.} and Baell, {Jonathan B.} and Stasch, {Johannes Peter} and Yorihiro Yamamoto and {Di Mascio}, Paolo and Philip Eaton and Payne, {Richard J.} and Roland Stocker",
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Stanley, CP, Maghzal, GJ, Ayer, A, Talib, J, Giltrap, AM, Shengule, S, Wolhuter, K, Wang, Y, Chadha, P, Suarna, C, Prysyazhna, O, Scotcher, J, Dunn, LL, Prado, FM, Nguyen, N, Odiba, JO, Baell, JB, Stasch, JP, Yamamoto, Y, Di Mascio, P, Eaton, P, Payne, RJ & Stocker, R 2019, 'Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation' Nature, vol. 566, no. 7745, pp. 548-552. https://doi.org/10.1038/s41586-019-0947-3

Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation. / Stanley, Christopher P.; Maghzal, Ghassan J.; Ayer, Anita; Talib, Jihan; Giltrap, Andrew M.; Shengule, Sudhir; Wolhuter, Kathryn; Wang, Yutang; Chadha, Preet; Suarna, Cacang; Prysyazhna, Oleksandra; Scotcher, Jenna; Dunn, Louise L.; Prado, Fernanda M.; Nguyen, Nghi; Odiba, Jephthah O.; Baell, Jonathan B.; Stasch, Johannes Peter; Yamamoto, Yorihiro; Di Mascio, Paolo; Eaton, Philip; Payne, Richard J.; Stocker, Roland.

In: Nature, Vol. 566, No. 7745, 28.02.2019, p. 548-552.

Research output: Contribution to journalLetterResearchpeer-review

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AU - Stanley, Christopher P.

AU - Maghzal, Ghassan J.

AU - Ayer, Anita

AU - Talib, Jihan

AU - Giltrap, Andrew M.

AU - Shengule, Sudhir

AU - Wolhuter, Kathryn

AU - Wang, Yutang

AU - Chadha, Preet

AU - Suarna, Cacang

AU - Prysyazhna, Oleksandra

AU - Scotcher, Jenna

AU - Dunn, Louise L.

AU - Prado, Fernanda M.

AU - Nguyen, Nghi

AU - Odiba, Jephthah O.

AU - Baell, Jonathan B.

AU - Stasch, Johannes Peter

AU - Yamamoto, Yorihiro

AU - Di Mascio, Paolo

AU - Eaton, Philip

AU - Payne, Richard J.

AU - Stocker, Roland

PY - 2019/2/28

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N2 - 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.

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Stanley CP, Maghzal GJ, Ayer A, Talib J, Giltrap AM, Shengule S et al. Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation. Nature. 2019 Feb 28;566(7745):548-552. https://doi.org/10.1038/s41586-019-0947-3