Details

Autor(en) / Beteiligte

• 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

Titel

Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation

Ist Teil von

• Nature (London), 2019-02, Vol.566 (7745), p.548-552

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. Singlet molecular oxygen, produced by indoleamine 2,3-dioxygenase 1 activity, gives rise to a signalling molecule that regulates arterial relaxation under inflammatory conditions.