| First Author | Stanley CP | Year | 2019 |
| Journal | Nature | Volume | 566 |
| Issue | 7745 | Pages | 548-552 |
| PubMed ID | 30760924 | Mgi Jnum | J:274321 |
| Mgi Id | MGI:6294800 | Doi | 10.1038/s41586-019-0947-3 |
| Citation | Stanley CP, et al. (2019) Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation. Nature 566(7745):548-552 |
| abstractText | Singlet molecular oxygen ((1)O2) has well-established roles in photosynthetic plants, bacteria and fungi(1-3), but not in mammals. Chemically generated (1)O2 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)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 of (1)O2. We observed that in the presence of hydrogen peroxide, the enzyme generates (1)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 G1alpha. Our findings demonstrate a pathophysiological role for (1)O2 in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions. |
