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Enhanced XOR activity in eNOS-deficient mice: Effects on the nitrate-nitrite-NO pathway and ROS homeostasis.
- Source :
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Free radical biology & medicine [Free Radic Biol Med] 2016 Oct; Vol. 99, pp. 472-484. Date of Electronic Publication: 2016 Sep 05. - Publication Year :
- 2016
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Abstract
- Xanthine oxidoreductase (XOR) is generally known as the final enzyme in purine metabolism and as a source of reactive oxygen species (ROS). In addition, this enzyme has been suggested to mediate nitric oxide (NO) formation via reduction of inorganic nitrate and nitrite. This NO synthase (NOS)-independent pathway for NO generation is of particular importance during certain conditions when NO bioavailability is diminished due to reduced activity of endothelial NOS (eNOS) or increased oxidative stress, including aging and cardiovascular disease. The exact interplay between NOS- and XOR-derived NO generation is not fully elucidated yet. The aim of the present study was to investigate if eNOS deficiency is associated with changes in XOR expression and activity and the possible impact on nitrite, NO and ROS homeostasis. Plasma levels of nitrate and nitrite were similar between eNOS deficient (eNOS <superscript>-/-</superscript> ) and wildtype (wt) mice. XOR activity was upregulated in eNOS <superscript>-/-</superscript> compared with wt, but not in nNOS <superscript>-/-</superscript> , iNOS <superscript>-/-</superscript> or wt mice treated with the non-selective NOS inhibitor L-NAME. Following an acute dose of nitrate, plasma nitrite increased more in eNOS <superscript>-/-</superscript> compared with wt, and this augmented response was abolished by the selective XOR inhibitor febuxostat. Livers from eNOS <superscript>-/-</superscript> displayed higher nitrite reducing capacity compared with wt, and this effect was attenuated by febuxostat. Dietary supplementation with nitrate increased XOR expression and activity, but concomitantly reduced superoxide generation. The latter effect was also seen in vitro after nitrite administration. Treatment with febuxostat elevated blood pressure in eNOS <superscript>-/-</superscript> , but not in wt mice. A high dose of dietary nitrate reduced blood pressure in naïve eNOS <superscript>-/-</superscript> mice, and again this effect was abolished by febuxostat. In conclusion, eNOS deficiency is associated with an upregulation of XOR facilitating the nitrate-nitrite-NO pathway and decreasing the generation of ROS. This interplay between XOR and eNOS is proposed to play a significant role in NO homeostasis and blood pressure regulation.<br /> (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Blood Pressure drug effects
Enzyme Inhibitors pharmacology
Febuxostat pharmacology
Gene Expression Regulation
Male
Mice
Mice, Knockout
NG-Nitroarginine Methyl Ester pharmacology
Nitrates blood
Nitrates pharmacology
Nitric Oxide Synthase Type I antagonists & inhibitors
Nitric Oxide Synthase Type I deficiency
Nitric Oxide Synthase Type II antagonists & inhibitors
Nitric Oxide Synthase Type II deficiency
Nitric Oxide Synthase Type III antagonists & inhibitors
Nitric Oxide Synthase Type III deficiency
Nitrites blood
Nitrites pharmacology
Oxidation-Reduction
Signal Transduction
Superoxides metabolism
Xanthine Dehydrogenase antagonists & inhibitors
Xanthine Dehydrogenase metabolism
Nitric Oxide blood
Nitric Oxide Synthase Type I genetics
Nitric Oxide Synthase Type II genetics
Nitric Oxide Synthase Type III genetics
Xanthine Dehydrogenase genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4596
- Volume :
- 99
- Database :
- MEDLINE
- Journal :
- Free radical biology & medicine
- Publication Type :
- Academic Journal
- Accession number :
- 27609225
- Full Text :
- https://doi.org/10.1016/j.freeradbiomed.2016.09.004