1. Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation.
- Author
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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, and Stocker R
- Subjects
- Animals, Cell Line, Cyclic GMP-Dependent Protein Kinase Type I antagonists & inhibitors, Cyclic GMP-Dependent Protein Kinase Type I chemistry, Cyclic GMP-Dependent Protein Kinase Type I metabolism, Cysteine metabolism, Enzyme Activation drug effects, Female, Humans, Hydrogen Peroxide chemistry, Hydrogen Peroxide metabolism, Hydrogen Peroxide pharmacology, Indoleamine-Pyrrole 2,3,-Dioxygenase chemistry, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism, Inflammation enzymology, Male, Oxidation-Reduction drug effects, Rats, Signal Transduction, Singlet Oxygen chemistry, Tryptophan chemistry, Tryptophan metabolism, Blood Pressure physiology, Inflammation blood, Inflammation physiopathology, Singlet Oxygen metabolism, Vasodilator Agents metabolism
- Abstract
Singlet molecular oxygen (
1 O2 ) has well-established roles in photosynthetic plants, bacteria and fungi1-3 , but not in mammals. Chemically generated1 O2 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 forms1 O2 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 of1 O2 . We observed that in the presence of hydrogen peroxide, the enzyme generates1 O2 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 for1 O2 in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions.- Published
- 2019
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