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Uric acid attenuates nitric oxide production by decreasing the interaction between endothelial nitric oxide synthase and calmodulin in human umbilical vein endothelial cells: A mechanism for uric acid-induced cardiovascular disease development

Title
Uric acid attenuates nitric oxide production by decreasing the interaction between endothelial nitric oxide synthase and calmodulin in human umbilical vein endothelial cells: A mechanism for uric acid-induced cardiovascular disease development
Authors
Park J.-H.Jin Y.M.Hwang S.Cho D.-H.Kang D.-H.Jo I.
Ewha Authors
강덕희조인호박정현
SCOPUS Author ID
강덕희scopus; 조인호scopus
Issue Date
2013
Journal Title
Nitric Oxide - Biology and Chemistry
ISSN
1089-8603JCR Link
Citation
vol. 32, pp. 36 - 42
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
The elevated level of uric acid in the body is associated with increased risk of cardiovascular diseases, which is mediated by endothelial dysfunction. However, its underlying mechanism is not fully understood, although dysregulation of endothelial nitric oxide (NO) production is likely to be involved. Using human umbilical vascular endothelial cells (HUVEC), we explored the molecular mechanism of uric acid on endothelial NO synthase (eNOS) activity and NO production. Although high dose of uric acid (12 mg/dl for 24 h treatment) significantly decreased eNOS activity and NO production, it did not alter eNOS expression and phosphorylations at eNOS-Ser1177, eNOS-Thr 495 and eNOS-Ser114. Under this condition, we also found no alterations in the dimerization and acetylation of eNOS, compared with the control. Furthermore, uric acid did not change the activity of arginase II, an enzyme degrading l-arginine, a substrate of eNOS, and intracellular level of calcium, a cofactor for eNOS activation. We also found that uric acid did not alter xanthine oxidase activity, suggesting no involvement of xanthine oxidase-derived O2- production in the observed inhibitory effects. In vitro and in cell coimmunoprecipitation studies, however, revealed that uric acid significantly decreased the interaction between eNOS and calmodulin (CaM), an eNOS activator, although it did not change the intracellular CaM level. Like in HUVEC, uric acid also decreased eNOS-CaM interaction in bovine aortic EC. Finally, uric acid attenuated ionomycin-induced increase in the interaction between eNOS and CaM. This study suggests firstly that uric acid decreased eNOS activity and NO production through reducing the binding between eNOS and CaM in EC. Our result may provide molecular mechanism by which uric acid induces endothelial dysfunction. © 2013 Elsevier Inc. All rights reserved.
DOI
10.1016/j.niox.2013.04.003
Appears in Collections:
의과대학 > 의학과 > Journal papers
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