Abstract 10334: Activation of NAD(P)H Oxidase by Tryptophan-derived 3-hydroxykynurenine Accelerates Endothelial Apoptosis and Dysfunction in vivo
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. However, the specific contribution of this pathway to endothelial cell death and the underlying regulatory mechanisms remain unknown.
Methods and Results: Endogenous reactive oxygen species (ROS), endothelial cell apoptosis, and endothelium-dependent and -independent vasorelaxation were measured in aortas of wild-type mice or mice deficient for nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase subunits (p47phox or gp91phox) or indoleamine 2,3-dioxygenase (IDO) with or without angiotensin (Ang) II infusion. As expected, AngII increased plasma levels of Kyns and 3-hydroxykynurenine (3-OHKyn)-modified proteins in endothelial cells in vivo. Consistent with this, AngII markedly increased the expression of IDO in parallel with increased expression of interferon-gamma, a potent inducer of IDO. Further, 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 p47phox, gp91phox or IDO, suggesting that AngII-induced enhancement of Kyns via NAD(P)H oxidase-derived oxidants causes endothelial cell apoptosis and dysfunction in vivo. Mechanistically, we found that AngII-enhanced 3-OHKyn 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 up-regulating NAD(P)H-derived superoxide.
- © 2013 by American Heart Association, Inc.