Increased nitric oxide bioavailability in endothelial cells contributes to the pleiotropic effect of cerivastatin
Increased nitric oxide bioavailability in endothelial cells contributes to the pleiotropic effect of cerivastatin
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DOI：
10.1161/hc0802.104283
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发表时间：
2002-02-26
期刊：
影响因子：
37.8
通讯作者：
Malinski, T
中科院分区：
文献类型：
--
作者：
Kalinowski, L;Dobrucki, LW;Malinski, T
背景-尽管他汀类药物通过降低血清胆固醇水平来保护内皮功能，但也有研究表明，他汀类药物可能刺激内皮中的一氧化氮（NO）合酶，同时增加超氧化物（O-2（-））的产生，导致NO活性受损。因此，在暴露于HMG-CoA还原酶抑制剂西立伐他汀后，进行内皮中生物活性NO和O-2（-）的测量以评估其对NO生物活性的潜在影响。方法和结果-将高灵敏度的电化学NO和O-2（-）微传感器放置在单个人脐静脉内皮细胞的表面附近，体外测定NO和O-2（-）释放动力学。西立伐他汀对内皮细胞NO释放具有时间依赖性作用。初始释放（约前3分钟）是浓度依赖性的（0.01至10 μ mol/L），并观察到典型的NO合酶激动剂钙离子载体或乙酰胆碱类似。西立伐他汀能促进NO的释放，清除O-2（-），维持NO的活性浓度。西立伐他汀对内皮细胞的持续作用（约6小时后）使NO释放较初始作用增加约35%。与初始效应相反，西立伐他汀的持续效应显示在浓度约为100倍低，并依赖于抑制内皮HMG-CoA reductase. Conclusions，这些数据提供了直接的证据证明，在西立伐他汀的存在下，内皮NOS系统的运作，通过激活NO释放和同时失活O-2（-）朝增加NO活性的高效率。
Background-Although statins preserve endothelial function by reducing serum cholesterol levels, it has been suggested they may also stimulate nitric oxide (NO) synthase in endothelium with concurrent increase in superoxide (O-2(-)) generation, leading to impairment of NO activity. Therefore, measurements of biologically active NO and O-2(-) in endothelium after exposure to the HMG-CoA reductase inhibitor cerivastatin were undertaken to evaluate its potential effect on NO biological activity.Methods and Results-Highly sensitive electrochemical NO and O-2(-) microsensors were placed near the surface of a single human umbilical vein endothelial cell, and the kinetics of NO and O-2(-) release were recorded in vitro. Cerivastatin demonstrated a time-dependent effect on NO release in endothelial cells. The initial release (approximately the first 3 minutes) was concentration-dependent (0.01 to 10 mumol/L) and was similar to that observed for typical NO synthase agonists calcium ionophore or acetylcholine. Cerivastatin stimulated NO release at a favorable rate and scavenged O-2(-), which led to the preservation of the active concentration of NO. The sustained effect (after approximate to6 hours) of cerivastatin on endothelium was associated with an approximate to35% increase in NO release as compared with the initial effect. In contrast to the initial effect, the sustained effect of cerivastatin was shown at concentrations approximate to100-fold lower and was dependent on inhibition of endothelial HMG-CoA reductase.Conclusions-These data provide direct evidence to prove that in the presence of cerivastatin, the NOS system in endothelium operates with high efficiency toward increasing NO activity by activation of NO release and by concurrent inactivation of O-2(-).