高尿酸血症与血管内皮损伤的基础与临床研究

【作者】 刘淑芬；

【导师】 曾学军；

【作者基本信息】 北京协和医学院 ， 内科学， 2011， 博士

【摘要】 背景：尿酸是嘌呤代谢产物,人类进化过程中尿酸酶基因突变,导致功能失活,使人的血尿酸水平较其它哺乳动物高。临床观察到高尿酸血症与心血管疾病有密切联系。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。多项研究显示血管内皮功能损伤是心血管疾病的重要始动因素,而关于尿酸影响血管内皮损伤的基础研究较少,尚存在一定分歧。目的：1)通过人群研究进一步证实高尿酸血症与其他代谢性疾病和心血管疾病的相关性,并探索单纯无症状性高尿酸血症人体内是否存在血管内皮功能损伤；2)利用尿酸酶抑制剂氧嗪酸钾升高大鼠血清尿酸水平,建立动物模型,并在动物模型观察单纯高尿酸对血管内皮功能的影响；3)通过建立长期高尿酸血症模型,观察单纯高尿酸血症能否造成大鼠主动脉及肾脏的病理变化。方法：1)多因素分析法分析2008年某体检人群病史、查体资料和生化检测指标,探讨高尿酸血症和各代谢异常的相关性；并选取单纯无症状性高尿酸血症94人,研究单纯无症状性高尿酸血症与血管内皮功能损伤的关系。2)使用2%的氧嗪酸饲料和1OOumol/L的尿酸水建立高尿酸血症动物模型,并使用别嘌醇阻止尿酸的升高,以NO、ET-1、ICAM作为血管内皮损伤的血清学指标,观察单纯升高尿酸对血管内皮损伤的影响。3)通过先使用2%的氧嗪酸饲料和1OOumol/L的尿酸水,后增加氧嗪酸灌胃的方法建立长期高尿酸血症动物模型,使用HE染色下内膜-中膜厚度、内皮炎性细胞浸润以及脂纹、脂斑的形成作为血管损伤的早期指标及肾叶间小动脉增殖、小动脉管壁增厚作为肾脏损伤的指标,分析高尿酸血症对大鼠主动脉及肾脏的病理变化,并通过对主动脉和肾脏的eNOS、ET-1、ICAM等的免疫组化染色和血清NO、ET-1、ICAM的检测进一步寻找血管损伤的证据。结果：1)人群高尿酸血症患病率14.3%,男性21.4%,女性11.5%；高尿酸血症组各代谢异常的患病率均较非高尿酸血症组高(P<0.01),在调整了年龄性别后差异仍有统计学意义；高尿酸血症增加各代谢异常的发生危险,多元Logistic回归分析后发现血清尿酸水平和肥胖、高血压、低HDL-C、高TG、脂肪肝显著独立相关。高尿酸血症组hs-CRP血清浓度较非高尿酸血症组明显高,差异有显著性(P<0.01)；但两组TNF-α浓度差异无显著性；高尿酸血症组血清NO浓度较非高尿酸血症人群明显降低(P<0.01),血清ET-1水平及ICAM水平均较非高尿酸血症人群明显升高(P<0.01)2)造模17天时单造模组ET-1、ICAM浓度较对照组升高,但无显著性差异,分别较单治疗组和造模+治疗组升高,提示高尿酸血症能够升高ET-1、ICAM,且降尿酸治疗,可以降低ET-1、ICAM:造模17天时单造模组NO浓度较对照组显著降低(P<0.05),分别较单治疗组和造模+治疗组降低,提示高尿酸血症能够降低NO浓度,且降尿酸治疗,可以使NO浓度恢复。3)模型组部分大鼠可见动脉壁内皮细胞内膜-中膜厚度轻度增加,但无显著性差异(P=0.067)；浸润于内膜的炎性细胞数轻度增多,差异无显著性(P=0.12)；模型组1只动物动脉内膜出现小脂斑,表现为大量泡沫细胞聚集成堆,周边可找到单核巨噬细胞。但病灶内未找到变性的胶原纤维。模型组主动脉内膜eNOS表达较对照组明显减少、ET-1、ICAM表达显著高于对照组(p<0.05),模型组肾脏小动脉增殖和小动脉管壁厚度较对照组明显增加；模型组ET-1、ICAM表达显著高于对照组,但eNOS表达两组间无显著性差异。结论：1)高尿酸血症与肥胖、高血压、高血糖、血脂紊乱、脂肪肝等多项代谢异常均有显著相关性,是其独立危险因素。单纯无症状高尿酸血症患者存在血管内皮功能损伤,高尿酸血症可能通过损伤血管内皮功能和刺激C反应蛋白的产生而参与高血压、血脂异常、糖尿病、冠心病等疾病的发生发展。2)短期高尿酸血症(2周)可以降低大鼠血清NO值,轻度升高ET-1和ICAM值。3)长期高尿酸血症(12周)可以造成S-D大鼠主动脉早期内皮损伤,但不能形成典型动脉粥样硬化,可以引起叶间小动脉增殖及小动脉管壁增厚,但短期内并未影响肾脏功能。更多还原

【Abstract】 Background. Uric acid is the product of purine metabolism; however, a relatively higher level of serum uric acid in human is observed than that in other mammals since genetic mutations. Hyperuricemia often comes with cardiovascular diseases. The incidences of cardiovascular disease are related to the elevation of serum uric acid in general population. The role of Endothelial dysfunction in cardiovascular diseases has been certified by many research. However, there are few reports on the effect of uric acid on endothelial dysfunction and some are contradictory.Objective.1) To invesgate the relationship of hyperuricemia and other metobolitic disorders in a group during the annual health examination and the role hyperuricemia in endothelial dysfunction.2) To study the the role hyperuricemia in endothelial dysfunction, in a hyperuricemia animal model made by feed with Oxonic Acid contaminated forage; 3) To identify if hyperuricemia can induce arota and kidney pathology through copy a continuous long-term hyperuricemia animal model.Methods.1) Multiple variance analyis of the association of hyperuricemia and other metabolitic disorder; Chose 94 pure asymptom hyperuricemia people as patient and 94 people with same age and gender as control to determine the role of hyperuricemia in endothelial dysfunction.2) Use 2%OA forage and 1OOumol/L uric acid to copy a hyperuricemia and use allopurinol as a blocker, chose NO, ET-1, ICAM as marks of endothelial dysfunction, to identify the mechanism of uric acid in endothelial dysfunction,,3) Use 2%OA forage and 1OOumol/L uric acid plus OA lavage to copy a continuous long-term hyperuricemia animal model, and eNOS, ET-1、ICAM expression in arota and kidney to find out the role of uric acid in cardiovascular diseases。Results.1) 14.5%people have hyperuricemia in the health examination. The hyperuricemia group has a high rate of ther metabolism dysfunction. Concentrate of serum uric acid has a strong association with age, gender, BMI.SysBp, DiaBp, HDL-C、LDL-C、TC、TG、nonHDL-C, Glu Cr、ALT、AIP、fatty liver by analyzing in bivariate correlation。Concentrate of serum uric acid was independently associated with obesity, hypertension, low HDL-C, hypertriglyceridemia, and fatty liver by analyzing in logistic multiple regression. The hs-CRP concentration is higher in the aymptom hyperuricemia, but no difference in TNF-αlevel between these two groups. The NO concentration is lower in the asymptom hyperuricemia group, whereas the ET-1 and ICAM level is higher in the aymptom hyperuricemia.2) Hyperuricemia rat has higer ET-1、ICAM level and lower NO concentration; Allopurinol can block the change at D17.3). Hyperuricemia rat has tiny damage whereas rats in control group is totally normal; Hyperuricemia rat has less eNOS expression, moreET-、ICAM expression in arota(p<0.05); Hyperuricemia rat has higher ET-1、ICAM expression than the control group while the same eNOS expression in kidney.Conclusion.1) Hyperuricemia was significantly associated with obesity, hypertension, low HDL-C, hypertriglyceridemia, and fatty liver, independently in the health examination group. Asymptom hyperuricemia can induce endothelial dysfunction.2) Short-term hyperuricemia has decrease the production of NO concentration in rat.3) Long-term hyperuricemia can induce mild pathology in rat arota and kidney.更多还原