TY - JOUR
T1 - Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation
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
Y1 - 2019/2/28
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.
AB -
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.
UR - http://www.scopus.com/inward/record.url?scp=85062059949&partnerID=8YFLogxK
U2 - 10.1038/s41586-019-0947-3
DO - 10.1038/s41586-019-0947-3
M3 - Letter
C2 - 30760924
AN - SCOPUS:85062059949
SN - 0028-0836
VL - 566
SP - 548
EP - 552
JO - Nature
JF - Nature
IS - 7745
ER -