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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.
Nature; 566(7745): 548-552, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30760924
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.
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