Enhanced XOR activity in eNOS-deficient mice Effects on the nitrate-nitrite-NO pathway and ROS homeostasis
2016 (English)In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 99, 472-484 p.Article in journal (Refereed) Published
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(-/-)) and wildtype (wt) mice. XOR activity was upregulated in eNOS(-/-) compared with wt, but not in nNOS(-/-), iNOS(-/-) or wt mice treated with the non-selective NOS inhibitor L-NAME. Following an acute dose of nitrate, plasma nitrite increased more in eNOS(-/-) compared with wt, and this augmented response was abolished by the selective XOR inhibitor febuxostat. Livers from eNOS(-/-) 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(-/-), but not in wt mice. A high dose of dietary nitrate reduced blood pressure in na ve eNOS(-/-) 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.
Place, publisher, year, edition, pages
2016. Vol. 99, 472-484 p.
Nitrate, Nitrite, Nitric oxide, Xanthine oxidase, Xanthine oxidoreductase, Febuxostat, Hypertension, Endothelial nitric oxide synthase, Oxidative stress, Reactive oxygen species, Superoxide, Uric acid
Endocrinology and Diabetes Cell Biology
IdentifiersURN: urn:nbn:se:uu:diva-310778DOI: 10.1016/j.freeradbiomed.2016.09.004ISI: 000387995400044PubMedID: 27609225OAI: oai:DiVA.org:uu-310778DiVA: diva2:1057887
FunderSwedish Research Council, 521-2011-2639Swedish Heart Lung Foundation, 20110589 20140448Knut and Alice Wallenberg Foundation, KAW 2015.0063Stockholm County Council