Uric acid-induced C-reactive protein expression: Implication on cell proliferation and nitric oxide production of human vascular cells
Uric acid-induced C-reactive protein expression: Implication on cell proliferation and nitric oxide production of human vascular cells
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DOI：
10.1681/asn.2005050572
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发表时间：
2005-12-01
影响因子：
13.6
通讯作者：
Johnson, RJ
中科院分区：
文献类型：
--
作者：
Kang, DH;Park, SK;Johnson, RJ
近期的实验研究和人体研究表明，高尿酸血症与高血压、全身性炎症以及由内皮功能障碍和病理性血管重塑介导的心血管疾病相关。C - 反应蛋白（CRP）水平升高已成为心血管疾病最有力的独立预测因子之一。除了作为炎症的标志物外，近期证据表明CRP可能直接参与动脉粥样硬化性血管疾病的发展。为了研究尿酸（UA）诱导的炎症反应和血管重塑是否与CRP相关，检测了UA诱导的人血管平滑肌细胞（HVSMC）和人脐静脉内皮细胞（HUVEC）中CRP的表达，以及CRP在血管重塑中的致病作用。有趣的是，HVSMC和HUVEC组成性地表达CRP mRNA和蛋白质，这表明血管细胞是CRP产生的另一个来源。UA（6 - 12mg/dl）上调了HVSMC和HUVEC中CRP mRNA的表达，同时CRP释放到细胞培养基中的量也增加。抑制p38或细胞外信号调节激酶44/42可显著抑制UA诱导的CRP表达，这表明这些通路参与了对UA的反应。通过H - 3 - 胸腺嘧啶核苷摄取和细胞计数评估发现，UA刺激HVSMC增殖，而抑制血清诱导的HUVEC增殖，与有机阴离子转运抑制剂丙磺舒共同孵育可减弱这种作用，这表明UA进入细胞是导致CRP表达的原因。UA还增加HVSMC的迁移并抑制HUVEC的迁移。在HUVEC中，UA减少一氧化氮（NO）的释放。用抗CRP抗体处理血管细胞显示，UA对HVSMC细胞增殖和迁移以及HUVEC中NO释放的影响被逆转，这表明CRP表达可能是UA诱导血管重塑的原因。这是第一项表明生理浓度的可溶性UA对人血管细胞有深远影响的研究。UA通过CRP表达改变人血管细胞的增殖/迁移和NO释放这一观察结果，要求我们仔细重新考虑UA在高血压和血管疾病中的作用。
Recent experimental and human studies have shown that hyperuricemia is associated with hypertension, systemic inflammation, and cardiovascular disease mediated by endothelial dysfunction and pathologic vascular remod eling. Elevated levels of C-reactive protein (CRP) have emerged as one of the most powerful independent predictors of cardiovascular disease. In addition to being a marker of inflammation, recent evidence suggests that CRP may participate directly in the development of atherosclerotic vascular disease. For investigating whether uric acid (UA)-induced inflammatory reaction and vascular remodeling is related to CRP, the UA-induced expression of CRP in human vascular smooth muscle cells (HVSMC) and human umbilical vein endothelial cells (HUVEC) was examined, as well as the pathogenetic role of CRP in vascular remodeling. It is interesting that HVSMC and HUVEC expressed CRP mRNA and protein consi:itutively, revealing that vascular cells are another source of CRP production. UA (6 to 12 mg/dI) upregulated CRP mRNA expression in HVSMC and HUVEC with a concomitant increase in CRP release into cell culture media. Inhibition of p38 or extracellular signal-regulated kinase 44/42 significantly suppressed UA-induced CRP expression, implicating these pathways in the response to UA. UA stimulated HVSMC proliferation whereas UA inhibited serum-induced proliferation of HUVEC assessed by H-3-thymidine uptake and cell counting, which was attenuated by co-incubation with probenecid, the organic anion transport inhibitor, suggesting that entry of UA into cells is responsible for CRP expression. UA also increased HVSMC migration and inhibited HUVEC migration. In HUVEC, UA reduced nitric oxide (NO) release. Treatment of vascular cells with anti-CRP antibody revealed a reversal of the effect of UA on cell proliferation and migration in HVSMC and NO release in HUVEC, which suggests that CRP expression may be responsible for UA-induced vascular remodeling. This is the first study to show that soluble UA, at physiologic concentrations, has profound effects on human vascular cells. The observation that UA alters the proliferation/migration and NO release of human vascular cells, mediated by the expression of CRP, calls for careful reconsideration of the role of UA in hypertension and vascular disease.