title: Activation of NAD(P)H oxidase by tryptophan-derived 3-hydroxykynurenine accelerates endothelial apoptosis and dysfunction in vivo.
abstract: BACKGROUND
  The kynurenine (Kyn) pathway is the major route for tryptophan (Trp) metabolism in mammals. The Trp-Kyn pathway is reported to regulate several fundamental biological processes, including cell death.
  
  
  OBJECTIVE
  The aim of this study was to elucidate the contributions and molecular mechanism of Trp-Kyn pathway to endothelial cell death.
  
  
  RESULTS
  Endogenous reactive oxygen species, endothelial cell apoptosis, and endothelium-dependent and endothelium-independent vasorelaxation were measured in aortas of wild-type mice or mice deficient for nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase subunits (p47(phox) or gp91(phox)) or indoleamine-pyrrole 2,3-dioxygenase 1 with or without angiotensin (Ang) II infusion. As expected, AngII increased plasma levels of Kyn- and 3-hydroxykynurenine-modified proteins in endothelial cells in vivo. Consistent with this, AngII markedly increased the expression of indoleamine-pyrrole 2,3-dioxygenase in parallel with increased expression of interferon-γ. Furthermore, in wild-type mice, AngII significantly increased oxidative stress, endothelial cell apoptosis, and endothelial dysfunction. These effects of AngII infusion were significantly suppressed in mice deficient for p47(phox), gp91(phox), or indoleamine-pyrrole 2,3-dioxygenase 1, suggesting that AngII-induced enhancement of Kynurenines via NAD(P)H oxidase-derived oxidants causes endothelial cell apoptosis and dysfunction in vivo. Furthermore, interferon-γ neutralization eliminates AngII-increased superoxide products and endothelial apoptosis by inhibiting AngII-induced Kynurenines generation, suggesting that AngII-activated Kyn pathway is interferon-γ-dependent. Mechanistically, we found that AngII-enhanced 3-hydroxykynurenine promoted the generation of NAD(P)H oxidase-mediated superoxide anions by increasing the translocation and membrane assembly of NAD(P)H oxidase subunits in endothelial cells, resulting in accelerated apoptosis and consequent endothelial dysfunction.
  
  
  CONCLUSIONS
  Kyn pathway activation accelerates apoptosis and dysfunction of the endothelium by upregulating NAD(P)H-derived superoxide.
authors.affiliation: From Division of Molecular Medicine, Department of Medicine, and Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Qiongxin
authors.initials: Q
authors.lastname: Wang
authors.forename: Miao
authors.initials: M
authors.lastname: Zhang
authors.forename: Ye
authors.initials: Y
authors.lastname: Ding
authors.forename: Qilong
authors.initials: Q
authors.lastname: Wang
authors.forename: Wencheng
authors.initials: W
authors.lastname: Zhang
authors.forename: Ping
authors.initials: P
authors.lastname: Song
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology* / Q000473:pathology*; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D007737:Kynurenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics
chemical_list: C005045:3-hydroxykynurenine; D007737:Kynurenine; D014364:Tryptophan; D019255:NADPH Oxidases
keywords: 3-hydroxykynurenine; NAD(P)H oxidase; apoptosis; indoleamine-pyrrole 2,3,-dioxygenase; kynurenine; oxidative stress; tryptophan