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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation

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Autor(es):
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Stanley, Christopher P. [1] ; Maghzal, Ghassan J. [1, 2] ; Ayer, Anita [1, 2] ; Talib, Jihan [1, 2] ; Giltrap, Andrew M. [3] ; Shengule, Sudhir [1] ; Wolhuter, Kathryn [1] ; Wang, Yutang [4, 5, 6] ; Chadha, Preet [1] ; Suarna, Cacang [1] ; Prysyazhna, Oleksandra [7, 8] ; Scotcher, Jenna [7, 8] ; Dunn, Louise L. [1] ; Prado, Fernanda M. [9] ; Nguyen, Nghi [10] ; Odiba, Jephthah O. [10] ; Baell, Jonathan B. [10, 11] ; Stasch, Johannes-Peter [12] ; Yamamoto, Yorihiro [13] ; Di Mascio, Paolo [9] ; Eaton, Philip [7, 8] ; Payne, Richard J. [3] ; Stocker, Roland [1, 2]
Número total de Autores: 23
Afiliação do(s) autor(es):
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[1] Victor Chang Cardiac Res Inst, Darlinghurst, NSW - Australia
[2] Univ New South Wales, St Vincents Clin Sch, Sydney, NSW - Australia
[3] Univ Sydney, Sch Chem, Sydney, NSW - Australia
[4] Univ Sydney, Sch Med Sci Pathol, Ctr Vasc Res, Sydney, NSW - Australia
[5] Univ Sydney, Sydney Med Sch, Bosch Inst, Sydney, NSW - Australia
[6] Federat Univ Australia, Sch Hlth & Life Sci, Ballarat, Vic - Australia
[7] Kings Coll London, Cardiovasc Div, Dept Cardiol, London - England
[8] St Thomas Hosp, Rayne Inst, London - England
[9] Univ Sao Paulo, Inst Quim, Dept Bioquim, Sao Paulo - Brazil
[10] Monash Univ, Monash Inst Pharmaceut Sci, Med Chem, Parkville, Vic - Australia
[11] Nanjing Tech Univ, Sch Pharmaceut Sci, Nanjing, Jiangsu - Peoples R China
[12] Bayer AG, Cardiovasc Res, Wuppertal - Germany
[13] Tokyo Univ Technol, Sch Biosci & Biotechnol, Tokyo - Japan
Número total de Afiliações: 13
Tipo de documento: Artigo Científico
Fonte: Nature; v. 566, n. 7745, p. 548+, FEB 28 2019.
Citações Web of Science: 5
Resumo

Singlet molecular oxygen (O-1(2)) has well-established roles in photosynthetic plants, bacteria and fungi(1-3), but not in mammals. Chemically generated O-1(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 O-1(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 O-1(2). We observed that in the presence of hydrogen peroxide, the enzyme generates O-1(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 G1 alpha. Our findings demonstrate a pathophysiological role for O-1(2) in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions. (AU)

Processo FAPESP: 12/12663-1 - Oxigênio singlete e peróxidos em química biológica
Beneficiário:Paolo Di Mascio
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 13/07937-8 - Redoxoma
Beneficiário:Ohara Augusto
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs