Singlet oxygen is the signal for vasodilation of blood vessels during serious inflammatory conditions

Sepsis is a life-threatening condition in which the body responds to an infection by producing widespread biochemical changes (e.g. a massive vasodilation) that make the situation worse — often leading to a dramatic fall in blood pressure (which can be fatal). What are the environmental “signals” that cause this to happen in our genome? Molecules that alter constriction of blood vessels include nitric oxide (NO), prostaglandins, and oxidants such as hydrogen peroxide (H2O2). In 2010, kynurenine (metabolite of tryptophan) was identified as another factor that causes blood vessels to dilate during sepsis.

Authors [see attached article] — from the same lab — are now correcting that story, concluding that kynurenine is not the culprit. This is what happens in science: conclusions in the past get corrected, based on new more accurate findings later.

Authors realized that kynurenine alone did not cause blood-vessel widening (vasodilation); however, a mixture of tryptophan — and either the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) or singlet oxygen (1O2), a reactive oxygen species (ROS) — generated by IDO1 [IDO1 expression is normally low in cell types other than immune cells, but becomes up-regulated by inflammatory signals (cytokines) and by redox stress]. Authors therefore searched for another vasodilator (that was being formed) and identified it by the very simple chemical name J of “(2S,3aR, 8aR)-3a-hydroperoxy-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid”, abbreviated as cis-WOOH. This is formed by IDO1 in a reaction involving tryptophan and 1O2, in the presence of H2O2.

“Conventional dogma” had said that “IDO1 activity is up-regulated by chemical reducing agents, and down-regulated by H2O2.” However, these authors [attached article] discovered that reducing agents did not generate cis-WOOH, whereas H2O2 exposure did. Authors determined that cis-WOOH activates protein kinase cGMP-dependent 1 (PRKG1; which has is a dimer, assembled from two identical protein monomers) — by oxidizing a specific cysteine amino-acid residue (Cys-42) in the enzyme; this causes a disulfide bond to form between the Cys42 residues in the two monomers of PRKG1. These data demonstrate a pathophysiological role (i.e. not a “good” physiological response, but rather an “undesirable” physiological outcome) for 1O2 in mammals — by means of the formation of an amino acid-derived hydroperoxide that regulates vascular tone, and therefore blood pressure, under conditions in which the environmental signal is “serious inflammation.”


Nature 28 Feb 2o19; 566: 548-552 [article] & pp 464-464 [News’N’View editorial]

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