尿酸降低培养的肺动脉内皮细胞NO的产生,提高精氨酸酶的活性。

PubMed ID
发表日期 2008年Nov月

原始出处 美国生理学杂志。细胞生理学
American journal of physiology. Cell physiology
作者 Zharikov  Sergey  Krotova  Karina  Hu  Hanbo  Baylis  Chris  Johnson  Richard J  Block  Edward R  Patel  Jawaharlal 

文献标题 尿酸降低培养的肺动脉内皮细胞NO的产生,提高精氨酸酶的活性。
Uric acid decreases NO production and increases arginase activity in cultured pulmonary artery endothelial cells.

文献摘要

血清尿酸水平升高通常与原发性肺动脉高压有关,但一般认为没有任何因果关系。然而,最近的实验研究表明,UA可能影响多种血管活性介质。因此,我们验证了UA可能改变肺动脉内皮细胞(PAEC)一氧化氮(NO)水平的假设。在离体猪肺动脉段(PAS)中,UA(7.5mg/dl)抑制乙酰胆碱诱导的血管舒张。PAEC与UA的孵育导致缓激肽或钙离子载体A23187刺激的NO和cGMP产生的剂量依赖性下降。我们探讨了UA可能导致NO生成减少的细胞机制,重点是UA对l-精氨酸-内皮一氧化氮合酶(eNOS)和l-精氨酸-精氨酸酶途径的影响。PAEC与不同浓度UA(2.5-15mg/dl)孵育24小时,对l-[(3)h]精氨酸摄取和eNOS活性/表达无影响。然而,与UA(7.5mg/dl;24h)共孵育的PAEC比对照PAEC释放更多的尿素,提示精氨酸酶的激活可能与UA的作用有关。PAEC裂解液和大鼠肝、肾匀浆中精氨酸酶活性的动力学分析表明,UA通过增强其对l-精氨酸的亲和力而激活精氨酸酶。精氨酸酶(S)-(2-硼乙基)-l-半胱氨酸抑制剂阻止了UA诱导PAEC减少A23187刺激的cGMP生成,并消除了UA诱导的对乙酰胆碱刺激的PAS血管舒张的抑制。我们认为UA诱导的精氨酸酶激活是PAEC中NO生成减少的潜在机制。


Elevated levels of serum uric acid (UA) are commonly associated with primary pulmonary hypertension but have generally not been thought to have any causal role. Recent experimental studies, however, have suggested that UA may affect various vasoactive mediators. We therefore tested the hypothesis that UA might alter nitric oxide (NO) levels in pulmonary arterial endothelial cells (PAEC). In isolated porcine pulmonary artery segments (PAS), UA (7.5 mg/dl) inhibits acetylcholine-induced vasodilation. The incubation of PAEC with UA caused a dose-dependent decrease in NO and cGMP production stimulated by bradykinin or Ca(2+)-ionophore A23187. We explored cellular mechanisms by which UA might cause reduced NO production focusing on the effects of UA on the l-arginine-endothelial NO synthase (eNOS) and l-arginine-arginase pathways. Incubation of PAEC with different concentrations of UA (2.5-15 mg/dl) for 24 h did not affect l-[(3)H]arginine uptake or activity/expression of eNOS. However, PAEC incubated with UA (7.5 mg/dl; 24 h) released more urea in culture media than control PAEC, suggesting that arginase activation might be involved in the UA effect. Kinetic analysis of arginase activity in PAEC lysates and rat liver and kidney homogenates demonstrated that UA activated arginase by increasing its affinity for l-arginine. An inhibitor of arginase (S)-(2-boronoethyl)-l-cysteine prevented UA-induced reduction of A23187-stimulated cGMP production by PAEC and abolished UA-induced inhibition of acetylcholine-stimulated vasodilation in PAS. We conclude that UA-induced arginase activation is a potential mechanism for reduction of NO production in PAEC.


获取全文 10.1152/ajpcell.00075.2008