期刊
CIRCULATION RESEARCH
卷 114, 期 3, 页码 480-492出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.114.302113
关键词
3-hydroxykynurenine; apoptosis; indoleamine-pyrrole 2; 3; -dioxygenase; kynurenine; NAD(P)H oxidase; oxidative stress; tryptophan
资金
- National Institutes of Health [HL110488, HL105157, HL096032, HL080499, HL089920, HL079584, HL074399]
- American Diabetes Association
- Warren Chair in Diabetes Research of the University of Oklahoma Health Science Center
- American Heart Association [11SDG5560036]
- National Established Investigator Award of the American Heart Association
Rationale: 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. Methods and 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-. 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- neutralization eliminates AngII-increased superoxide products and endothelial apoptosis by inhibiting AngII-induced Kynurenines generation, suggesting that AngII-activated Kyn pathway is interferon--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.
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