尿酸与人脐静脉血管内皮细胞功能的体外研究
摘要
背景:尿酸是嘌呤代谢产物,人类因基因突变而使人的血尿酸水平较其它哺乳动物高。近年发现血尿酸水平升高与临床多种系统性疾病特别是血管性、代谢性疾病有密切联系。临床流行病研究发现,人群中随血尿酸水平升高,心血管疾病和代谢综合征等的发病率随之升高。基础研究中对尿酸影响血管内皮细胞功能的观点分歧较大,或认为高尿酸通过抑制NO生成而引起血管内皮细胞障碍并最终启动动脉粥样硬化进程;或黄嘌呤氧化酶催化次黄嘌呤和黄嘌呤生成尿酸的同时产生氧自由基而破坏了血管内皮细胞功能;或认为血尿酸更类似一种抗氧化物质,可以清除自由基,对内皮具有保护作用;或认为低浓度血尿酸对血管内皮有保护性作用,高浓度血尿酸对内皮特别是已经损伤的内皮有加速破坏的作用。
目的:通过不同浓度尿酸(UA)对人体脐静脉内皮细胞(HUVEC)的体外刺激,测定氧化产物ROS和抗氧化反应中人内皮细胞一氧化氮合成酶(eNOS) mRNA的表达情况,初步测定体外一定浓度尿酸刺激血管内皮细胞一定时间后,对内皮细胞功能的影响。
方法:MTT细胞活力检测实验测定不同时间经不同浓度尿酸培养HUVEC之间活力的差异;共聚焦荧光显微镜检测不同浓度尿酸刺激HUVEC 48小时后细胞ROS的表达;流式细胞仪检测不同浓度尿酸刺激HUVEC 48小时后细胞ROS的表达;RT-PCR检测不同浓度尿酸刺激HUVEC 48小时候后eNOS mRNA的表达水平;Real-Time PCR检测不同浓度尿酸刺激HUVEC 48小时候后eNOS mRNA的表达水平。
结果:在不同浓度尿酸(0、5、10、20和30mg/dL)中培养不同时间(8、12、24和48h)之后,MTT检测发现第8h和12h时各个尿酸浓度组HUVEC的活力之间没有差异,第24h和48h时各个尿酸浓度组HUVEC的活力较对照组有显著降低(P＜0.05)。HUVEC经体外不同浓度尿酸(0、5、10、20和30mg/dL)刺激48h后,经激光共聚焦显微镜检测发现HUVEC胞浆中DCFDA探针标记的ROS表达灰度强度与尿酸刺激浓度呈显著正相关(P＜0.001)。同时HUVEC经体外不同浓度尿酸(0、5、10、20、30mg/dL)刺激48h后,采用RT-PCR检测细胞中eNOS mRNA的表达,发现eNOS mRNA的表达强度与尿酸培养浓度亦呈显著正相关(P＜0.05)。
结论:初步研究发现,体外HUVEC在不同浓度尿酸中培养不同时间后,MTT法测得第24h和48h时各个尿酸浓度组HUVEC的活力较对照组有显著降低。体外实验中,随着外源性尿酸浓度升高,HUVEC胞浆中ROS的表达程度升高,提示高浓度外源性尿酸刺激对HUVEC内皮细胞功能可能具有损伤作用。体外HUVEC被不同浓度尿酸刺激后eNOS mRNA表达增加,不排除是机体对尿酸激活ROS后产生的抗氧化反应所致。
Background.Uric acid is the product of metabolism of purine;however,a relatively higher level of serum uric acid in human is observed than that in any other mammals since a genetic mutation is detected in human genomes.The level of serum uric acid is reported to be associated with many systemic diseases such as vascular and metabolic diseases in recent years.The incidences of cardiovascular disease and metabolic diseases are related to the elevation of serum uric acid in general population,reported by clinical and epidemiological researches.However,different and diverse opinions rise from laboratory researches on the effects of serum uric acid on the endothelial function.Some reported that the endothelial dysfunction could be induced by inhibiting the NO production by hyperuricemia and then initiate the process of arthrosclerosis. Another group of research indicated that it was ROS,which was generated as a by-product from xanthine by xanthine oxidase during the production of uric acid, caused the endothelial dysfunction.A third opinion thought the serum acid can erase the ROS and thus regarded as a protective factor in maintaining the endothelial function.Finally,another group of study indicated that a lower level of serum uric acid could provide protective effect on vascular endothelium while a higher level of serum uric acid could accelerated the destruction of vascular endothelial,especially when it had already been injured.
Objective.To determine the production of ROS and the expression of eNOS mRNA in Human Umbilical Vein Endothelial Cells(HUVEC) stimulated by uric acid solution with stratified concentrations for a certain duration in vitro,in order to study the effects on endothelial dysfunction by uric acid with different concentrations.
Methods.MTT test for cell viability on HUVEC stimulated by uric acid of stratified concentrations in different time point.Confocul Fluorescent Microscopy scanning for ROS production in HUVEC after a 48h co-culture in uric acid at stratified concentrations.Flow Cytometry test for ROS production in HUVEC after a 48h co-culture in uric acid at stratified concentrations.RT-PCR amplification for the test and comparison of eNOS mRNA expression in HUVEC after a 48h co-culture in uric acid at stratified concentrations.Real-Time PCR amplification and detection for the comparison of eNOS mRNA expression in HUVEC stimulated by uric acid of stratified concentrations.
Results.HUVEC viability had no significant decrease with the increase of uric acid(0、5、10、20、30mg/dL) in 8h and 12h;however,significant differences among groups of different uric acid concentrations were discovered after 24h and 48h culture of HUVEC.The mean intensity of ROS expression in HUVEC in vitro after 48h co-culture with uric acid was significantly positively related to the concentration of uric acid applied.The increase of eNOS mRNA production in HUVEC in vitro after 48h co-culture with uric acid was significantly positively related to the increase of uric acid concentration.
Conclusion.In this study,viability of HUVEC in vitro had significant difference between groups after 24h and 48h co-culture with uric acid of different concentrations.ROS expression increased with the elevation of exogeneous uric acid concentration in HUVEC in vitro,indicating that endothelial function may be impaired by uric acid in a higher concentration.eNOS mRNA production incrased with the increase of exogenous uric acid concentration.A response as an antioxidant reaction against the activation of ROS should be taken into concern.
目的:通过不同浓度尿酸(UA)对人体脐静脉内皮细胞(HUVEC)的体外刺激,测定氧化产物ROS和抗氧化反应中人内皮细胞一氧化氮合成酶(eNOS) mRNA的表达情况,初步测定体外一定浓度尿酸刺激血管内皮细胞一定时间后,对内皮细胞功能的影响。
方法:MTT细胞活力检测实验测定不同时间经不同浓度尿酸培养HUVEC之间活力的差异;共聚焦荧光显微镜检测不同浓度尿酸刺激HUVEC 48小时后细胞ROS的表达;流式细胞仪检测不同浓度尿酸刺激HUVEC 48小时后细胞ROS的表达;RT-PCR检测不同浓度尿酸刺激HUVEC 48小时候后eNOS mRNA的表达水平;Real-Time PCR检测不同浓度尿酸刺激HUVEC 48小时候后eNOS mRNA的表达水平。
结果:在不同浓度尿酸(0、5、10、20和30mg/dL)中培养不同时间(8、12、24和48h)之后,MTT检测发现第8h和12h时各个尿酸浓度组HUVEC的活力之间没有差异,第24h和48h时各个尿酸浓度组HUVEC的活力较对照组有显著降低(P＜0.05)。HUVEC经体外不同浓度尿酸(0、5、10、20和30mg/dL)刺激48h后,经激光共聚焦显微镜检测发现HUVEC胞浆中DCFDA探针标记的ROS表达灰度强度与尿酸刺激浓度呈显著正相关(P＜0.001)。同时HUVEC经体外不同浓度尿酸(0、5、10、20、30mg/dL)刺激48h后,采用RT-PCR检测细胞中eNOS mRNA的表达,发现eNOS mRNA的表达强度与尿酸培养浓度亦呈显著正相关(P＜0.05)。
结论:初步研究发现,体外HUVEC在不同浓度尿酸中培养不同时间后,MTT法测得第24h和48h时各个尿酸浓度组HUVEC的活力较对照组有显著降低。体外实验中,随着外源性尿酸浓度升高,HUVEC胞浆中ROS的表达程度升高,提示高浓度外源性尿酸刺激对HUVEC内皮细胞功能可能具有损伤作用。体外HUVEC被不同浓度尿酸刺激后eNOS mRNA表达增加,不排除是机体对尿酸激活ROS后产生的抗氧化反应所致。
Background.Uric acid is the product of metabolism of purine;however,a relatively higher level of serum uric acid in human is observed than that in any other mammals since a genetic mutation is detected in human genomes.The level of serum uric acid is reported to be associated with many systemic diseases such as vascular and metabolic diseases in recent years.The incidences of cardiovascular disease and metabolic diseases are related to the elevation of serum uric acid in general population,reported by clinical and epidemiological researches.However,different and diverse opinions rise from laboratory researches on the effects of serum uric acid on the endothelial function.Some reported that the endothelial dysfunction could be induced by inhibiting the NO production by hyperuricemia and then initiate the process of arthrosclerosis. Another group of research indicated that it was ROS,which was generated as a by-product from xanthine by xanthine oxidase during the production of uric acid, caused the endothelial dysfunction.A third opinion thought the serum acid can erase the ROS and thus regarded as a protective factor in maintaining the endothelial function.Finally,another group of study indicated that a lower level of serum uric acid could provide protective effect on vascular endothelium while a higher level of serum uric acid could accelerated the destruction of vascular endothelial,especially when it had already been injured.
Objective.To determine the production of ROS and the expression of eNOS mRNA in Human Umbilical Vein Endothelial Cells(HUVEC) stimulated by uric acid solution with stratified concentrations for a certain duration in vitro,in order to study the effects on endothelial dysfunction by uric acid with different concentrations.
Methods.MTT test for cell viability on HUVEC stimulated by uric acid of stratified concentrations in different time point.Confocul Fluorescent Microscopy scanning for ROS production in HUVEC after a 48h co-culture in uric acid at stratified concentrations.Flow Cytometry test for ROS production in HUVEC after a 48h co-culture in uric acid at stratified concentrations.RT-PCR amplification for the test and comparison of eNOS mRNA expression in HUVEC after a 48h co-culture in uric acid at stratified concentrations.Real-Time PCR amplification and detection for the comparison of eNOS mRNA expression in HUVEC stimulated by uric acid of stratified concentrations.
Results.HUVEC viability had no significant decrease with the increase of uric acid(0、5、10、20、30mg/dL) in 8h and 12h;however,significant differences among groups of different uric acid concentrations were discovered after 24h and 48h culture of HUVEC.The mean intensity of ROS expression in HUVEC in vitro after 48h co-culture with uric acid was significantly positively related to the concentration of uric acid applied.The increase of eNOS mRNA production in HUVEC in vitro after 48h co-culture with uric acid was significantly positively related to the increase of uric acid concentration.
Conclusion.In this study,viability of HUVEC in vitro had significant difference between groups after 24h and 48h co-culture with uric acid of different concentrations.ROS expression increased with the elevation of exogeneous uric acid concentration in HUVEC in vitro,indicating that endothelial function may be impaired by uric acid in a higher concentration.eNOS mRNA production incrased with the increase of exogenous uric acid concentration.A response as an antioxidant reaction against the activation of ROS should be taken into concern.
引文
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2 Capasso,G.,et al.,Uric acid and the kidney:urate transport,stone disease and progressive renal.failure.Curr Pharm Des,2005.11(32):p.4153-9.
3 Wu,X.W.,et al.,Two independent mutational events in the loss o.f urate oxidase during hominoid evolution.J Mol Evol,1992.34(1):p.78-84.
4 Nakagawa,T.,et al.,A causal role.for uric acid in.fructose-induced metabolic syndrome.Am J Physiol Renal Physiol,2006.290(3):p.F625-31.
5 Yu,K.H.,et al.,Dietary factors associated with hyperuricemia in adults.Semin Arthritis Rheum,2008.37(4):p.243-50.
6 Cairo-Villas,J.M.,et al.,Acute tumor lysis syndrome during oral fludarabine treatment for chronic lymphocytic leukemia.Role o.f treatment with rasbuficase.Onkologie,2008.31(4):p.197-9.
7 Suh,W.M.,et al.,Acute lymphoblastic leukemia presenting as acute renal failure.Nat Clin Pract Nephrol,2007.3(2):p.106-10.
8 Torres,R.J.and J.G.Puig,Hypoxanthine-guanine phosophoribosyltransferase(HPRT)deficiency:Lesch-Nyhan syndrome.Orphanet J Rare Dis,2007.2:p.48.
9 Avram,Z.and E.Krishnan,Hyperuricaemia--where nephrology meets rheumatology.Rheumatology(Oxford),2008.
10 Strazzullo,P.,et al.,Altered renal sodium handling in men with abdominal adiposity:a link to hypertension.J Hypertens,2001.19(12):p.2157-64.
11 Puig,J.G.and L.M.Ruilope,Uric acid as a cardiovascular risk factor in arterial hypertension.J Hypertens,1999.17(7):p.869-72.
12 Quinones Galvan,A.,et al.,Effect of insulin on uric acid excretion in humans.Am J Physiol,1995.268(1 Pt 1):p.E1-5.
13 Cappuccio,F.R,et al.,Uric acid metabolism and tubular sodium handling.Results from a population-based study,lAMA,1993.270(3):p.354-9.
14 Strazzullo,R,et al.,Abnormalities of renal sodium handling in the metabolic syndrome.Results of the Olivetti Heart Study.J Hypertens,2006.24(8):p.1633-9.
15 Strazzullo,R,et al.,Use of fractional lithium clearance in clinical and epidemiological investigation:a methodological assessment.Clin Sci(Lond),1988.74(6):p.651-7.
16 Reyes,A.J.and W.R Leary,The increase in serum uric acid induced by diuretics could be beneficial to cardiovascular prognosis in hypertension:a hypothesis.J Hypertens,2003.21(9):p.1775-7.
17 Glantzounis,G.K.,et al.,Uric acid and oxidative stress.Curr Pharm Des,2005.11(32):p.4145-51.
18 Johnson,R.J.,et al.,Uric acid,evolution and primitive cultures.Semin Nephrol,2005.2S(1):p.3-8.
19 Mikkelsen WM.The distribution of serum uric acid values in a population unselected as to gout or hyperuricemia.Tecumseh,Michigan.1959-1960.Am J Med 1965;39:242-251
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1 Garrod,A.,The Nature of and treatment of gout and rheumatic gout.2nd ed.London:Walton and Maberly.1863.
2 Capasso,G.,et al.,Uric acid and the kidney:urate transport,stone disease and progressive renal failure.Curr Pharm Des,2005.11(32):p.4153-9.
3 Wu,X.W.,et al.,Two independent mutational events in the loss of urate oxidase during hominoid evolution.J Mol Evol,1992.34(1):p.78-84.
4 Naka8awa,T.,et al.,A causal role,for uric acid in,fructose-induced metabolic syndrome.Am J Physiol Renal Physiol,2006.290(3}:p.F625-31.
5 Yu,K.H.,et al.,Dietary,factors associated with hyperuricemia in adults.Semin Arthritis Rheum,2008.37(4):p.243-50.
6 Cairo-Villas,J.M.,et al.,Acute tumor lysis syndrome during oral fludarabine treatment.for chronic lymphocytic leukemia.Role of treatment with rasburicase.Onkologie,2008.31(4):p.197-9.
7 Suh,W.M.,et al.,Acute lymphoblastic leukemia presenting as acute renal failure.Nat Clin Pract Nephrol,2007.3(2):p.106-10.
8 Torres,R.J.and J.G.Puig,Hypoxanthine-guanine phosophoribosyltransferase(HPRT) deficiency:Lesch-Nyhan syndrome.Orphanet J Rare Dis,2007.2:p.48.
9 Avram,Z.and E.Krishnan,Hyperuricaemia--where nephrology meets rheumatology.Rheumatology(Oxford),2008.
10 Strazzullo,R,et al.,Altered renal sodium handling in men with abdominal adiposity:a link to hypertension.J Hypertens,2001.19(12):p.2157-64.
11 Puig,J.G.and L.M.Ruilope,Uric acid as a cardiovascular risk factor in arterial hypertension.J Hypertens,1999.17(7):p.869-72.
12 Quinones Galvan,A.,et al.,Effect of insulin on uric acid excretion in humans.Am J Physiol,1995.268(1 Pt 1):p.E1-5.
13 Cappuccio,ER,et al.,Uric acid metabolism and tubular sodium handlins.Results from a population-based study.JAMA,1993.270(3):p.354-9.
14 Strazzullo,R,et al.,Abnormalities of renal sodium handling in the metabolic syndrome.Results of the Olivetti Heart Study.J Hypertens,2006.24(8):p.1633-9.
15 Strazzullo,R,et al.,Use of fractional lithium clearance in clinical and epidemiolosical investigation:a methodological assessment.Clin Sci(Lond),1988.74(6):p.651-7.
16 Reyes,A.J.and W.R Leary,The increase in serum uric acid induced by diuretics could be beneficial to cardiovascular prognosis in hypertension:a hypothesis.J Hypertens,2003.21(9):p.1775-7.
17 Glantzounis,G.K.,et al.,Uric acid and oxidative stress.Curt Pharm Des,2005.11(32):p.4145-51.
18 Roubenoff,R.,Gout and hyperuricemia.Rheum Dis Clin North Am,1990.16(3):p.539-50.
19 Johnson,R.J.,et al.,Uric acid,evolution and primitive cultures.Semin Nephrol,2005.25(1):p.3-8.
20 Mikkelsen WM.The distribution of serum uric acid values in a population unselected as to gout or hyperuricemia.Tecumseh,Michisan.1959-1960.Am J Med 1965;39:242-251
21 Glynn,R.J.,E.W.Campion,and J.E.Silbert,Trends in serum uric acid levels 2951--1980.Arthritis Rheum,1983.26(1):p.87-93.
22 Persky,V.W.,et al.,Uric acid:a risk factor for coronary heart disease? Circulation,1979.59(5):p.969-77.
23 Brand,F.N.,et al.,Hyperuricemia as a risk.factor of coronary heart disease:The Framingham Study.Am J Epidemiol,1985.121(1):p.11-8.
24 Culleton,B.F.,et al.,Serum uric acid and risk for cardiovascular disease and death:the Framingham Heart Study.Ann Intern Med,1999.131(1):p.7-13.
25 Fang,J.and M.H.Alderman,Serum uric acid and cardiovascular mortality the NHANESI epidemiologic follow-up study,1971-1992.National Health and Nutrition Examination Survey.JAMA,2000.283(18):p.2404-10.
26 M azza,A.,et al.,Predictors of stroke mortality in elderly people from the general population.The CArdiovascular STudy in the ELderly.Eur J Epidemiol,2001.17(12):p.1097-104.
27 Puddu,P.E.,et al.,Serum uric acid for short-term prediction of cardiovascular disease incidence in the Gubbio population Study.Acta Cardiol,2001.56(4):p.243-51.
28 Niskanen,L.K.,et al.,Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men:a prospective cohort study.Arch Intern Med,2004.164(14):p.1546-51.
29 Johnson,R.J.,et al.,Resurrection of uric acid as a causal risk factor in essential hypertension.Hypertension,2005.45(1):p.18-20.
30 Nakagawa,T.,et al.,Hypothesis:fructose-induced hyperuricemia as a causal mechanism for the epidemic of the metabolic syndrome.Nat Clin Pract Nephrol,2005.1(2):p.80-6.
31 Hu,P.,et al.,Is serum uric acid level associated with all-cause mortality in high-functioning older persons:MacArthur studies of successful aging? J Am Geriatr Soc,2001.49(12):p.1679-84.
32 Jee,S.H.,S.Y.Lee,and M.T.Kim,Serum uric acid and risk of death from cancer,cardiovascular disease or all causes in men.Eur J Cardiovasc Prev Rehabil,2004.11(3):p.185-91.
33 Lehto,S.,et al.,Serum uric acid is a strong predictor of stroke in patients with non-insulin-dependent diabetes mellitus.Stroke,1998.29(3):p.635-9.
34 Bickel,C.,et al.,Serum uric acid as an independentpredictor of mortality in patients with angiographically proven coronary artery disease.Am J Cardiol,2002.89(1):p.12-7.
35 Weir,C.J.,et al.,Serum urate as an independent predictor of poor outcome and future vascular events after acute stroke.Stroke,2003.34(8):p.1951-6.
36 Anker,S.D.,et al.,Uric acid and survival in chronic heart failure:validation and application in metabolic,functional and hemodynamic staging.Circulation,2003.107(15):p.1991-7.
37 Choi,H.K.and E.S.Ford,Prevalence of the metabolic syndrome in individuals with hyperuricemia.Am J Med,2007.120(5):p.442-7
38 Rho,Y.H.,et al.,Association between serum uric acid and the Adult Treatment Panel Ⅲ-defined metabolic syndrome:results from a single hospital database.Metabolism,2008.57(1):p.71-6.
39 Lohsoonthorn,V.,B.Dhanamun,and M.A.Williams,Prevalence of hyperuricemia and its relationship with metabolic syndrome in Thai adults receiving annual health exams.Arch Med Res,2006.37(7):p.883-9.
40 Ishizaka,N.,et al.,Association between serum uric acid,metabolic syndrome,and carotid atherosclerosis in Japanese individuals.Arterioscler Thromb Vasc Biol,2005.25(5):p.1038-44.
41 Kawamoto,R.,et al.,Relationship between serum uric acid concentration,metabolic syndrome and carotid atherosclerosis.Intern Mad,2006.45(9):p.605-14.
42 Bonora,E.,et al.,Hyperinsulinemia and insulin resistance are independently associated with plasma lipids,uric acid and blood pressure in non-diabetic subjects.The GISIR database.Nutr Metab Cardiovasc Dis,2007
43 Nakagawa,T.,et al.,The conundrum of hyperuricemia,metabolic syndrome,and renal disease.Intern Emerg Med,2008.
44 Bainbridge,S.A.and J.M.Roberts,Uric acid as a pathogenic,factor in preeclampsia.Placenta,2008.29 Suppl A:p.S67-72.
45 Strazzullo,P.and J.G.Puig,Uric acid and oxidative stress:relative impact on cardiovascular risk? Nutr Metab Cardiovasc Dis,2007.17(6):p.409-14.
46 Khosla,U.M.,et al.,Hyperuricemia induces endothelial dysfunction.Kidney Int,2005.67(5):p.1739-42.
47 Berry,C.E.and J.M.Hare,Xanthine oxidoreductase and cardiovascular disease:molecular mechanisms and pathophysiological implications.J Physiol,2004.555(Pt 3):p.589-606.
48 Farquharson,C.A.,et al.,Allopurinol improves endothelial dysfunction in chronic heart failure.Circulation,2002.106(2):p.221-6.
49 Doehner,W.,et al.,Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure:results from 2 placebo-controlled studies.Circulation,2002.105(22):p.2619-24.
50 Butler,R.,et al.,Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension.Hypertension,2000.35(3):p.746-51.
51 Johnson,R.J.,et al.,Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension,2003.41(6):p.1183-90.
52 Mazza,A.,et al.,Predictors of stroke mortality in elderly people from the general population.The CArdiovascular STudy in the ELderly.Eur J Epidemiol,2001.17(12):p.1097-104.
53 Kanabrocki,E.L.,et al.,Circadian relationship of serum uric acid and nitric oxide.JAMA,2000.283(17):p.2240-1.
54 Orowan,E.,The origin of man.Nature,1955.175(4459):p.683-4.
55 Brooks,G.W.and E.Mueller,Serum urate concentrations among university professors;relation to drive,achievement,and leadership.JAMA,1966.195(6):p.415-8.
56 Kasl,S.V.,G.W.Brooks,and S.Cobb,Serum urate concentrations in male high-school students.JAMA,1966.198(7):p.713-6.
57 Glantzounis,G.K.,et al.,Uric acid and oxidative stress.Curr Pharm Des,2005.11(32):p.4145-51.
58 Waring,W.S.,et al.,Uric acid restores endothelial function in patients with type 1diabetes and regular smokers.Diabetes,2006.55(11):p.3127-32.
59 Ames,B.N.,et al.,Uric acid provides an antioxidant defense in humans against oxidant-and radical-caused aging and cancer:a hypothesis.Proc Natl Acad Sci U S A,1981.78(11):p.6858-62.
60 Waring,W.S.,D.J.Webb,and S.R.Maxwell,Systemic uric acid administration increases serum antioxidant capacity in healthy volunteers.J Cardiovasc Pharmacol,2001.38(3):p.365-71.
61 Chevion,S.,et al.,Plasma antioxidant status and cell injury after severe physical exercise.Proc Natl Acad Sci U S A,2003.100(9):p.5119-23.
62 Hellsten,Y.,et al.,Allantoin formation and urate and glutathione exchange in human muscle during submaximal exercise.Free Radic Biol Med,2001.31(11):p.1313-22.
63 Lehto,S.,et al.,Serum uric acid is a strong predictor of stroke in patients with non-insulin-dependent diabetes mellitus.Stroke,1998.29(3):p.635-9.
64 Wong,K.Y.,et al.,Urate predicts subsequent cardiac death in stroke survivors.Eur Heart J,2002.23(10):p.788-93.
65 Anker,S.D.,et al.,Uric acid and survival in chronic heart failure:validation and application in metabolic,functional,and hemodynamic staging.Circulation,2003.107(15):p.1991-7.
66 Bickel,C.,et al.,Serum uric acid as an independent predictor of mortality in patients with angiographically proven coronary artery disease.Am J Cardiol,2002.89(1):p.12-7.
2 Capasso,G.,et al.,Uric acid and the kidney:urate transport,stone disease and progressive renal.failure.Curr Pharm Des,2005.11(32):p.4153-9.
3 Wu,X.W.,et al.,Two independent mutational events in the loss o.f urate oxidase during hominoid evolution.J Mol Evol,1992.34(1):p.78-84.
4 Nakagawa,T.,et al.,A causal role.for uric acid in.fructose-induced metabolic syndrome.Am J Physiol Renal Physiol,2006.290(3):p.F625-31.
5 Yu,K.H.,et al.,Dietary factors associated with hyperuricemia in adults.Semin Arthritis Rheum,2008.37(4):p.243-50.
6 Cairo-Villas,J.M.,et al.,Acute tumor lysis syndrome during oral fludarabine treatment for chronic lymphocytic leukemia.Role o.f treatment with rasbuficase.Onkologie,2008.31(4):p.197-9.
7 Suh,W.M.,et al.,Acute lymphoblastic leukemia presenting as acute renal failure.Nat Clin Pract Nephrol,2007.3(2):p.106-10.
8 Torres,R.J.and J.G.Puig,Hypoxanthine-guanine phosophoribosyltransferase(HPRT)deficiency:Lesch-Nyhan syndrome.Orphanet J Rare Dis,2007.2:p.48.
9 Avram,Z.and E.Krishnan,Hyperuricaemia--where nephrology meets rheumatology.Rheumatology(Oxford),2008.
10 Strazzullo,P.,et al.,Altered renal sodium handling in men with abdominal adiposity:a link to hypertension.J Hypertens,2001.19(12):p.2157-64.
11 Puig,J.G.and L.M.Ruilope,Uric acid as a cardiovascular risk factor in arterial hypertension.J Hypertens,1999.17(7):p.869-72.
12 Quinones Galvan,A.,et al.,Effect of insulin on uric acid excretion in humans.Am J Physiol,1995.268(1 Pt 1):p.E1-5.
13 Cappuccio,F.R,et al.,Uric acid metabolism and tubular sodium handling.Results from a population-based study,lAMA,1993.270(3):p.354-9.
14 Strazzullo,R,et al.,Abnormalities of renal sodium handling in the metabolic syndrome.Results of the Olivetti Heart Study.J Hypertens,2006.24(8):p.1633-9.
15 Strazzullo,R,et al.,Use of fractional lithium clearance in clinical and epidemiological investigation:a methodological assessment.Clin Sci(Lond),1988.74(6):p.651-7.
16 Reyes,A.J.and W.R Leary,The increase in serum uric acid induced by diuretics could be beneficial to cardiovascular prognosis in hypertension:a hypothesis.J Hypertens,2003.21(9):p.1775-7.
17 Glantzounis,G.K.,et al.,Uric acid and oxidative stress.Curr Pharm Des,2005.11(32):p.4145-51.
18 Johnson,R.J.,et al.,Uric acid,evolution and primitive cultures.Semin Nephrol,2005.2S(1):p.3-8.
19 Mikkelsen WM.The distribution of serum uric acid values in a population unselected as to gout or hyperuricemia.Tecumseh,Michigan.1959-1960.Am J Med 1965;39:242-251
2o Glynn,R.J.,E.W.Campion,and J.E.Silbert,Trends in serum uric acid levels 1961-1980.Arthritis Rheum,1983.26(1):p.87-93.
21 Persky,V.W.,et al.,Uric acid:a risk fector for coronary heert diseese? Circulation,1979.59(5):p.969-77.
22 Brand,F.N.,et al.,Hyperuricernie es a risk fector of coronary heart diseese:The Framingham Study.Am J Epidemiol,1985.121(1):p.11-8.
23 Culleton,B.F.,et al.,Serum uric acid and risk for cardiovascular disaase end death:the Framingham Heart Study.Ann Intern Med,1999.131(1):p.7-13.
24 Choi,H.K.and E.S.Ford,Prevalence of the metabolic syndrome in individuals with hyperuricemia.Am J Med,2007.120(5):p.442-7
25 Rho,Y.H.,et al.,Association between serum uric ecid and the Adult Treetment Panel Ill-defined metabolic syndrome:results from a single hospitel database.Metabolism,2008.57(1)." p.71-6.
26 Lohsoonthorn,V.,B.Dhanamun,and M.A.Williams,Prevalence of hyperuricemla and its reletionship with metabolic syndrome in Thai adults receiving annual heelth exams.Arch Med Res,2006.37(7):p.883-9.
27 Ishizaka,N.,et al.,Association between serum uric acid,metebolic syndrome,and carotid atherosclerosis in Japenese individuals.Arterioscler Thromb Vasc Biol,2005.25(5):p.1038-44.
28 Kawamoto,R.,et al.,Relationship between serum uric acid concentretion,metabolic syndrome and cerotid atherosclerosis.Intern Med,2006.45(9):p.605-14.
29 Strazzullo,P.and J.G.Puig,Uric acid and oxidative stress:relative impact on cardiovascular risk? Nutr Metab Cardiovasc Dis,2007.17(6):p.409-14.
30 Khosla,U.M.,et al.,Hyperuricemia induces endothelial dysfunction.Kidney Int,2005.67(5):p.1739-42.
31 Berry,C.E.and J.M.Hare,Xanthine oxidoreductase and cardiovascular disease:molecular mechanisrns and pethophysiological implications.J Physiol,2004.555(Pt 3):p.589-606.
32 Glantzounis,G.K.,et al.,Uric acid and oxidative stress.Curr Pharm Des,2005.11.(32):p.4145-51.
33 Waring,W.S.,D.J.Webb,and S.R.Maxwell,Systemic uric ecid administration increases serum antioxidant capacity in healthy volunteers.J Cardiovasc Pharmacol,2001.38(3):p.365-71.
34 Chevion,S.,et al.,Plasme antioxidant status end cell injury after severe physical exercise.Proc Natl Acad Sci U S A,2003.100(9):p.5119-23.
35 Hellsten,Y.,et al.,Allantoin formation and urate and glutathione exchange in hurnan muscle during submeximal exercise.Free Radic Biol Med,2001.31(11):p.1313-22.
36 Xie,L.,et al.,Mitochondrial DNA oxidative damage triggers mitochondrial dysfunction and apoptosis in high glucose-induced human retinal vascular endothelial cells.Invest Ophthalmol Vis Sci,2008.
37 Sandalio,L.M.,et al.,Imaging of reactive oxygen species and nitric oxide in viva in plant tissues.Methods Enzymol,2008.440:p.397-409.
38 Niwa,K.,et al.,Roles o.f protein kinase C delta in the accumulation of P53 and the induction of apoptosis in H202-treated bovine endothelial cells.Free Radic Res,2002.36(11):p.1147-53.
39 Griendling,K.K.and G.A.FitzGerald,Oxidative stress and cardiovascular injury:Part Ⅰ:basic mechanisms and in viva monitoring ajaR05.Circulation,2003.108(16):p.1912-6.
40 Griendling,K.K.and G.A.FitzGerald,Oxidative stress and cardiovascular injury:Part Ⅱ:animal and human studies.Circulation,2003.108(17):p.2034-40.
41 Berk,B.C.,Novel approaches to treat oxidative stress and cardiovascular diseases.Trans Am Clin Climatol Assoc,2007.118:p.209-14.
42 Khosla,U.M.,et al.,Hyperuricemia induces endothelial dysfunction.Kidney Int,2005.67(5):p.1739-42.
43 Kang,D.H.,et al.,Uric acid-induced C-reactive protein expression:implication on cell proliferation and nitric oxide production of human vascular cells.J Am 5oc Nephrol,2005.16(12):p.3553-62.
44 Hennekens CH.,Buring JE,Epidemiology in Medicine 1~(st) Ed.,Little,Brown and Company,Boston,1995.
45 Nakagawa,T.,et al.,Hypothesis:fructose-induced hyperuricemia as a causal mechanism.for the epidemic of the metabofic syndrome.Nat Clin Pract Nephrol,2005.1(2):p.80-6.
46 Khosla,U.M.,et al.,Hyperuricemia induces endothelial dysfunction.Kidney Int,2005.67(5):p.1739-42.
47 Kang,D.H.,et al.,Uric acid-induced C-reactive protein expression:implication on cell proliferation and nitric oxide production of human vascular cells.J Am Sac Nephrol,2005.16(12):p.3553-62.
48 Davignon,J.and P.Ganz,Role of endothelial dysfunction in atherosclerosis.Circulation,2004.109(23 Suppl 1):p.11127-32.
49 Cai,H.and D.G.Harrison,Endothelial dys,function in cardiovascular diseases:the role o,foxidant stress.Clrc Res,2000.87(10):p.840-4.
50 George,J.and A.D.Struthers,The role of urate and xanthine oxidase inhibitors in cardiovascular disease.Cardiovasc Ther,2008.26(1):p.59-64.
51 Behrendt,D.and P.Ganz,Endothelial.function.From vascular biology to clinical appfications.Am J Cardiol,2002.90(10C):p.40L-48L.
52 Fang,J.C.,et al.,Circulating autoantibodies to oxidized LDL correlate with impaired coronary endothelial,function after cardiac transplantation.Arterioscler Thromb Vasc Biol,2002.22(12):p.2044-8.
1 Garrod,A.,The Nature of and treatment of gout and rheumatic gout.2nd ed.London:Walton and Maberly.1863.
2 Capasso,G.,et al.,Uric acid and the kidney:urate transport,stone disease and progressive renal failure.Curr Pharm Des,2005.11(32):p.4153-9.
3 Wu,X.W.,et al.,Two independent mutational events in the loss of urate oxidase during hominoid evolution.J Mol Evol,1992.34(1):p.78-84.
4 Naka8awa,T.,et al.,A causal role,for uric acid in,fructose-induced metabolic syndrome.Am J Physiol Renal Physiol,2006.290(3}:p.F625-31.
5 Yu,K.H.,et al.,Dietary,factors associated with hyperuricemia in adults.Semin Arthritis Rheum,2008.37(4):p.243-50.
6 Cairo-Villas,J.M.,et al.,Acute tumor lysis syndrome during oral fludarabine treatment.for chronic lymphocytic leukemia.Role of treatment with rasburicase.Onkologie,2008.31(4):p.197-9.
7 Suh,W.M.,et al.,Acute lymphoblastic leukemia presenting as acute renal failure.Nat Clin Pract Nephrol,2007.3(2):p.106-10.
8 Torres,R.J.and J.G.Puig,Hypoxanthine-guanine phosophoribosyltransferase(HPRT) deficiency:Lesch-Nyhan syndrome.Orphanet J Rare Dis,2007.2:p.48.
9 Avram,Z.and E.Krishnan,Hyperuricaemia--where nephrology meets rheumatology.Rheumatology(Oxford),2008.
10 Strazzullo,R,et al.,Altered renal sodium handling in men with abdominal adiposity:a link to hypertension.J Hypertens,2001.19(12):p.2157-64.
11 Puig,J.G.and L.M.Ruilope,Uric acid as a cardiovascular risk factor in arterial hypertension.J Hypertens,1999.17(7):p.869-72.
12 Quinones Galvan,A.,et al.,Effect of insulin on uric acid excretion in humans.Am J Physiol,1995.268(1 Pt 1):p.E1-5.
13 Cappuccio,ER,et al.,Uric acid metabolism and tubular sodium handlins.Results from a population-based study.JAMA,1993.270(3):p.354-9.
14 Strazzullo,R,et al.,Abnormalities of renal sodium handling in the metabolic syndrome.Results of the Olivetti Heart Study.J Hypertens,2006.24(8):p.1633-9.
15 Strazzullo,R,et al.,Use of fractional lithium clearance in clinical and epidemiolosical investigation:a methodological assessment.Clin Sci(Lond),1988.74(6):p.651-7.
16 Reyes,A.J.and W.R Leary,The increase in serum uric acid induced by diuretics could be beneficial to cardiovascular prognosis in hypertension:a hypothesis.J Hypertens,2003.21(9):p.1775-7.
17 Glantzounis,G.K.,et al.,Uric acid and oxidative stress.Curt Pharm Des,2005.11(32):p.4145-51.
18 Roubenoff,R.,Gout and hyperuricemia.Rheum Dis Clin North Am,1990.16(3):p.539-50.
19 Johnson,R.J.,et al.,Uric acid,evolution and primitive cultures.Semin Nephrol,2005.25(1):p.3-8.
20 Mikkelsen WM.The distribution of serum uric acid values in a population unselected as to gout or hyperuricemia.Tecumseh,Michisan.1959-1960.Am J Med 1965;39:242-251
21 Glynn,R.J.,E.W.Campion,and J.E.Silbert,Trends in serum uric acid levels 2951--1980.Arthritis Rheum,1983.26(1):p.87-93.
22 Persky,V.W.,et al.,Uric acid:a risk factor for coronary heart disease? Circulation,1979.59(5):p.969-77.
23 Brand,F.N.,et al.,Hyperuricemia as a risk.factor of coronary heart disease:The Framingham Study.Am J Epidemiol,1985.121(1):p.11-8.
24 Culleton,B.F.,et al.,Serum uric acid and risk for cardiovascular disease and death:the Framingham Heart Study.Ann Intern Med,1999.131(1):p.7-13.
25 Fang,J.and M.H.Alderman,Serum uric acid and cardiovascular mortality the NHANESI epidemiologic follow-up study,1971-1992.National Health and Nutrition Examination Survey.JAMA,2000.283(18):p.2404-10.
26 M azza,A.,et al.,Predictors of stroke mortality in elderly people from the general population.The CArdiovascular STudy in the ELderly.Eur J Epidemiol,2001.17(12):p.1097-104.
27 Puddu,P.E.,et al.,Serum uric acid for short-term prediction of cardiovascular disease incidence in the Gubbio population Study.Acta Cardiol,2001.56(4):p.243-51.
28 Niskanen,L.K.,et al.,Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men:a prospective cohort study.Arch Intern Med,2004.164(14):p.1546-51.
29 Johnson,R.J.,et al.,Resurrection of uric acid as a causal risk factor in essential hypertension.Hypertension,2005.45(1):p.18-20.
30 Nakagawa,T.,et al.,Hypothesis:fructose-induced hyperuricemia as a causal mechanism for the epidemic of the metabolic syndrome.Nat Clin Pract Nephrol,2005.1(2):p.80-6.
31 Hu,P.,et al.,Is serum uric acid level associated with all-cause mortality in high-functioning older persons:MacArthur studies of successful aging? J Am Geriatr Soc,2001.49(12):p.1679-84.
32 Jee,S.H.,S.Y.Lee,and M.T.Kim,Serum uric acid and risk of death from cancer,cardiovascular disease or all causes in men.Eur J Cardiovasc Prev Rehabil,2004.11(3):p.185-91.
33 Lehto,S.,et al.,Serum uric acid is a strong predictor of stroke in patients with non-insulin-dependent diabetes mellitus.Stroke,1998.29(3):p.635-9.
34 Bickel,C.,et al.,Serum uric acid as an independentpredictor of mortality in patients with angiographically proven coronary artery disease.Am J Cardiol,2002.89(1):p.12-7.
35 Weir,C.J.,et al.,Serum urate as an independent predictor of poor outcome and future vascular events after acute stroke.Stroke,2003.34(8):p.1951-6.
36 Anker,S.D.,et al.,Uric acid and survival in chronic heart failure:validation and application in metabolic,functional and hemodynamic staging.Circulation,2003.107(15):p.1991-7.
37 Choi,H.K.and E.S.Ford,Prevalence of the metabolic syndrome in individuals with hyperuricemia.Am J Med,2007.120(5):p.442-7
38 Rho,Y.H.,et al.,Association between serum uric acid and the Adult Treatment Panel Ⅲ-defined metabolic syndrome:results from a single hospital database.Metabolism,2008.57(1):p.71-6.
39 Lohsoonthorn,V.,B.Dhanamun,and M.A.Williams,Prevalence of hyperuricemia and its relationship with metabolic syndrome in Thai adults receiving annual health exams.Arch Med Res,2006.37(7):p.883-9.
40 Ishizaka,N.,et al.,Association between serum uric acid,metabolic syndrome,and carotid atherosclerosis in Japanese individuals.Arterioscler Thromb Vasc Biol,2005.25(5):p.1038-44.
41 Kawamoto,R.,et al.,Relationship between serum uric acid concentration,metabolic syndrome and carotid atherosclerosis.Intern Mad,2006.45(9):p.605-14.
42 Bonora,E.,et al.,Hyperinsulinemia and insulin resistance are independently associated with plasma lipids,uric acid and blood pressure in non-diabetic subjects.The GISIR database.Nutr Metab Cardiovasc Dis,2007
43 Nakagawa,T.,et al.,The conundrum of hyperuricemia,metabolic syndrome,and renal disease.Intern Emerg Med,2008.
44 Bainbridge,S.A.and J.M.Roberts,Uric acid as a pathogenic,factor in preeclampsia.Placenta,2008.29 Suppl A:p.S67-72.
45 Strazzullo,P.and J.G.Puig,Uric acid and oxidative stress:relative impact on cardiovascular risk? Nutr Metab Cardiovasc Dis,2007.17(6):p.409-14.
46 Khosla,U.M.,et al.,Hyperuricemia induces endothelial dysfunction.Kidney Int,2005.67(5):p.1739-42.
47 Berry,C.E.and J.M.Hare,Xanthine oxidoreductase and cardiovascular disease:molecular mechanisms and pathophysiological implications.J Physiol,2004.555(Pt 3):p.589-606.
48 Farquharson,C.A.,et al.,Allopurinol improves endothelial dysfunction in chronic heart failure.Circulation,2002.106(2):p.221-6.
49 Doehner,W.,et al.,Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure:results from 2 placebo-controlled studies.Circulation,2002.105(22):p.2619-24.
50 Butler,R.,et al.,Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension.Hypertension,2000.35(3):p.746-51.
51 Johnson,R.J.,et al.,Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension,2003.41(6):p.1183-90.
52 Mazza,A.,et al.,Predictors of stroke mortality in elderly people from the general population.The CArdiovascular STudy in the ELderly.Eur J Epidemiol,2001.17(12):p.1097-104.
53 Kanabrocki,E.L.,et al.,Circadian relationship of serum uric acid and nitric oxide.JAMA,2000.283(17):p.2240-1.
54 Orowan,E.,The origin of man.Nature,1955.175(4459):p.683-4.
55 Brooks,G.W.and E.Mueller,Serum urate concentrations among university professors;relation to drive,achievement,and leadership.JAMA,1966.195(6):p.415-8.
56 Kasl,S.V.,G.W.Brooks,and S.Cobb,Serum urate concentrations in male high-school students.JAMA,1966.198(7):p.713-6.
57 Glantzounis,G.K.,et al.,Uric acid and oxidative stress.Curr Pharm Des,2005.11(32):p.4145-51.
58 Waring,W.S.,et al.,Uric acid restores endothelial function in patients with type 1diabetes and regular smokers.Diabetes,2006.55(11):p.3127-32.
59 Ames,B.N.,et al.,Uric acid provides an antioxidant defense in humans against oxidant-and radical-caused aging and cancer:a hypothesis.Proc Natl Acad Sci U S A,1981.78(11):p.6858-62.
60 Waring,W.S.,D.J.Webb,and S.R.Maxwell,Systemic uric acid administration increases serum antioxidant capacity in healthy volunteers.J Cardiovasc Pharmacol,2001.38(3):p.365-71.
61 Chevion,S.,et al.,Plasma antioxidant status and cell injury after severe physical exercise.Proc Natl Acad Sci U S A,2003.100(9):p.5119-23.
62 Hellsten,Y.,et al.,Allantoin formation and urate and glutathione exchange in human muscle during submaximal exercise.Free Radic Biol Med,2001.31(11):p.1313-22.
63 Lehto,S.,et al.,Serum uric acid is a strong predictor of stroke in patients with non-insulin-dependent diabetes mellitus.Stroke,1998.29(3):p.635-9.
64 Wong,K.Y.,et al.,Urate predicts subsequent cardiac death in stroke survivors.Eur Heart J,2002.23(10):p.788-93.
65 Anker,S.D.,et al.,Uric acid and survival in chronic heart failure:validation and application in metabolic,functional,and hemodynamic staging.Circulation,2003.107(15):p.1991-7.
66 Bickel,C.,et al.,Serum uric acid as an independent predictor of mortality in patients with angiographically proven coronary artery disease.Am J Cardiol,2002.89(1):p.12-7.