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Xanthine Oxidase and NADPH Oxidase Induce Cardiovascular Endothelial Dysfunction During Hyperuricemia
Author(s) -
Zhang Suhua,
Huang Harer,
Serpillon Sabrina,
Wang Ziping,
Yu Xiaohan,
Hintze Thomas H.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.758.27
Subject(s) - apocynin , allopurinol , xanthine oxidase , nadph oxidase , hyperuricemia , xanthine oxidase inhibitor , endocrinology , medicine , uric acid , chemistry , endothelial dysfunction , nitrotyrosine , pharmacology , nitric oxide , biochemistry , oxidative stress , nitric oxide synthase , enzyme
Hyperuricemia(HU) induces cardiovascular diseases associated with O 2 − production through the activation of xanthine oxidase(XO). We hypothesized that HU can induce cardiovascular endothelial dysfunction and that both XO and NADPH oxidase are involved. Three groups of SD male rats, control(C), oxonic acid(OA‐ a uricase inhibitor) and OA + allopurinol(OAA) were studied for five weeks. In the OA group, serum uric acid (SUA, mg/dl) was significantly increased (2.5 ± 0.3 vs. 0.8 ± 0.1 in C, 1.9 ± 0.1 in OAA); Systolic blood pressure(SBP, mmHg) was elevated (170 ± 4.4 vs. 144 ± 1.1 in C, 157 ± 2.8 in OAA). There was a linear correlation between SUA and SBP (R 2 = 0.82). The total peripheral resistance by echocardiography was increased (P<0.05). The ability of the NO agonists BK and Cch to reduce myocardial O 2 consumption (MVO 2 ) was impaired (to 15% for BK or 20% for Cch vs.25% in C) in vitro. However, this was reversed by allopurinol administered in vivo, and restored in the presence of allopurinol, apocynin or tempol in vitro. Western blots of left ventricle showed that the protein p47, nitrotyrosine and P‐p38/p38 ratio were upregulated ( P < 0.05, respectively). HU enhanced bioactivity of XO and also NADPH oxidase, by a mechanism involving the activation of p47 protein and p38 kinase. NO is consumed via reaction with O 2 − and subsequently the ability of NO to control MVO 2 and endothelium‐dependent vasorelaxation was attenuated. Supported by HL‐PO1‐43023 grant.