Hyperuricemia induces endothelial dysfunction.
By U. Khosla, Sergey I Zharikov, Jennifer Finch, T. Nakagawa, Carlos Roncal, W. Mu, K. Krotova, E. Block, S. Prabhakar, Richard J. Johnson. Kidney International, 2005
1,235 citations recorded by the source corpus.
BACKGROUND Hyperuricemia has been linked to cardiovascular and renal diseases, possibly through the generation of reactive oxygen species (ROS) and subsequent endothelial dysfunction. The enzymatic effect of xanthine oxidase is the production of ROS and uric acid. Studies have shown that inhibiting xanthine oxidase with allopurinol can reverse endothelial dysfunction. Furthermore, rat studies have shown that hyperuricemia-induced hypertension and vascular disease is at least partially reversed by the supplementation of the nitric oxide synthase (NOS) substrate, L-arginine. Therefore, we hypothesized that uric acid induces endothelial dysfunction by inhibiting nitric oxide production. METHODS Hyperuricemia was induced in male Sprague-Dawley rats with an uricase inhibitor, oxonic acid, by gavage; control rats received vehicle. Allopurinol was placed in drinking water to block hyperuricemia. Rats were randomly divided into four groups: (1) control, (2) allopurinol only, (3) oxonic acid only, and (4) oxonic acid + allopurinol. Rats were sacrificed at 1 and 7 days, and their serum analyzed for serum uric acid and nitrites/nitrates concentrations. The effect of uric acid on nitric oxide production was also determined in bovine aortic endothelial cells. RESULTS Oxonic acid induced mild hyperuricemia at both 1 and 7 days (P < 0.05). Allopurinol reversed the hyperuricemia at 7 days (P < .001). Serum nitrites and nitrates (NO(X)) were reduced in hyperuricemic rats at both 1 and 7 days (P < .001). Allopurinol slightly reversed the decrease in NO(X) at 1 day and completely at 7 days (P < .001). There was a direct linear correlation between serum uric acid and NO(X) (R(2)= 0.56) and a trend toward higher systolic blood pressure in hyperuricemic rats (P= NS). Uric acid was also found to inhibit both basal and vascular endothelial growth factor (VEGF)-induced nitric oxide production in bovine aortic endothelial cells. CONCLUSION Hyperuricemic rats have a decrease in serum nitric oxide which is reversed by lowering uric acid levels. Soluble uric acid also impairs nitric oxide generation in cultured endothelial cells. Thus, hyperuricemia induces endothelial dysfunction; this may provide insight into a pathogenic mechanism by which uric acid may induce hypertension and vascular disease.
Subfields: Endocrinology, Diabetes and Metabolism, Nephrology
View Paper: https://www.semanticscholar.org/paper/42ba06494860032b013808fae1535a8f007d00dd
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Citations in the corpus
- Uric Acid: The Oxidant-Antioxidant Paradox (2008, background): “[34] On the other hand, uric acid in vitro decreased NO bioavailability in bovine aortic endothelial cells[31] as well as adipocytes.”
- Fructose consumption as a risk factor for non-alcoholic fatty liver disease. (2008, background): “There is also increasing evidence that the rise in uric acid may also have a potential role in causing features of the metabolic syndrome [18], in part by the ability of uric acid to deplete endothelial nitric oxide levels [45] and by activating the adipocyte [32].”
- Uric acid and inflammatory markers. (2006, background): “Briefly, in inflammatory related diseases chronic hypoxia causes cellular damage that upregulates the XO enzyme, leading to parallel increase of UA and free radicals production,(58) resulting into endothelial dysfunction.(59) Cytokines (TNF-a, IL-1, and IFN-g) may increase the UA production through ”
- Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. (2007, background): “Uric acid potently reduces the concentrations of endothelial nitric oxide in vitro and in vivo in experimental animals (64, 65).”
- Therapeutic Effects of Xanthine Oxidase Inhibitors: Renaissance Half a Century after the Discovery of Allopurinol (2006, background): “(Khosla et al., 2005).”
- Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. (2007, background): “In endothelial cells, uric acid decreases NO bioavailability (27, 30) and inhibits cell migration and proliferation, which are mediated in part by the expression of C-reactive protein (27).”