Department of Pharmacology and Toxicology, Karl-Franzens University Graz, Univ-Platz 2, A-8010 Graz, Austria.
Pharmacol Rep. 2010 Jan-Feb;62(1):100-12. doi: 10.1016/s1734-1140(10)70247-4.
Human umbilical vein endothelial cells (HUVECs) were established as in vitro models for the modulation of endothelial function and cell viability by statins. Emphasis was placed on the biphasic effects of the drugs on nitric oxide (NO) bioavailability and cytotoxicity, as well as drug interference with the interaction of endothelial NO synthase (eNOS) with caveolin-1 (Cav-1). Incubation of HUVECs with fluvastatin, lovastatin or cerivastatin for 24 h caused an approximately 3-fold upregulation of eNOS expression that was associated with increased eNOS activity and accumulation of cGMP. Cerivastatin exhibited the highest potency with an EC50 of 13.8 +/- 2 nM after 24 h, while having no effect after only 30 min. The effects of statins on eNOS expression were similar in control and Cav-1 knockdown cells, but the increase in eNOS activity was less pronounced in Cav-1-deficient cells. Statin-triggered cytotoxicity occurred at approximately 10-fold higher drug concentrations (maximal toxicity at 1-10 microM), was sensitive to mevalonate, and was significantly enhanced in the presence of NG-nitro-L-arginine. The overexpression of eNOS induced by clinically relevant concentrations of statins may contribute to the beneficial vascular effects of the drugs in patients. Stimulation of NO synthesis and cytotoxicity appear to share a common initial mechanism but involve distinct downstream signaling cascades that exhibit differential sensitivity to HMG-CoA reductase inhibition.
人脐静脉内皮细胞（HUVEC）被建立为体外模型，用于调节他汀类药物对内皮功能和细胞活力的影响。重点研究了药物对一氧化氮（NO）生物利用度和细胞毒性的双相作用，以及药物对内皮型一氧化氮合酶（eNOS）与 caveolin-1（Cav-1）相互作用的干扰。将 HUVEC 与氟伐他汀、洛伐他汀或西立伐他汀孵育 24 小时会导致 eNOS 表达增加约 3 倍，这与 eNOS 活性增加和 cGMP 积累有关。西立伐他汀在 24 小时后表现出最高的效力，EC50 为 13.8 +/- 2 nM，而在 30 分钟后没有效果。他汀类药物对 eNOS 表达的影响在对照和 Cav-1 敲低细胞中相似，但在 Cav-1 缺陷细胞中，eNOS 活性的增加不那么明显。他汀类药物触发的细胞毒性发生在大约 10 倍更高的药物浓度（最大毒性在 1-10 microM），对甲羟戊酸敏感，并且在存在 NG-硝基-L-精氨酸的情况下显著增强。临床相关浓度的他汀类药物诱导的 eNOS 过表达可能有助于药物对患者的有益血管作用。NO 合成的刺激和细胞毒性似乎具有共同的初始机制，但涉及不同的下游信号级联，对 HMG-CoA 还原酶抑制的敏感性不同。
