HMG CoA reductase inhibitors affect the fibrinolytic system of human vascular cells<b><i>in vitro</i></b>: a comparative study using different statins
作者:Franz Wiesbauer、Christoph Kaun、Gerlinde Zorn、Gerald Maurer、Kurt Huber、Johann Wojta
DOI:10.1038/sj.bjp.0704454
日期:2002.1
The results of several clinical studies investigating the effect of statin therapy on the fibrinolytic system in vivo are inconclusive. We compared the effect of six different statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, simvastatin) on components of the fibrinolytic system expressed by human vascular endothelial cells and smooth muscle cells and by the human hepatoma cell line HepG2.
All statins used except pravastatin significantly decreased PAI‐1 production in human endothelial and smooth muscle cells. This effect was also seen in the presence of IL‐1α and TNF‐α. All statins except pravastatin increased t‐PA production in human smooth muscle cells. On a molar basis cerivastatin was the most effective HMG CoA reductase inhibitor used. Only simvastatin and lovastatin increased t‐PA production in endothelial cells. The effects on the fibrinolytic system were reversed by mevalonate. Statins decreased mRNA levels for PAI‐1 in endothelial and smooth muscle cells and increased mRNA levels for t‐PA in smooth muscle cells. Statins did not affect PAI‐1 expression in HepG2 cells. Cell viability was not influenced by statins in endothelial cells and HepG2 cells whereas in smooth muscle cells a cytotoxic effect was seen at high concentrations.
If the effects on the fibrinolytic system of vascular cells in vitro shown in this study are also operative in vivo one could speculate that by increasing t‐PA and decreasing PAI‐1 at sites of vascular lesions statins might reduce fibrin formation and thrombus development. Such an effect might contribute to the clinically proven benefits of statin therapy.
British Journal of Pharmacology (2002) 135, 284–292; doi:10.1038/sj.bjp.0704454
多项临床研究调查了他汀类药物疗法对纤维蛋白溶解系统的影响,但结果尚无定论。我们比较了六种不同他汀类药物(阿托伐他汀、西立伐他汀、氟伐他汀、洛伐他汀、普伐他汀、辛伐他汀)对人血管内皮细胞和平滑肌细胞以及人肝癌细胞系HepG2所表达的纤维蛋白溶解系统成分的影响。
除普伐他汀外,所有使用的他汀类药物均显著减少了人内皮细胞和平滑肌细胞中的PAI-1产生。这一效应在IL-1α和TNF-α存在时亦观察到。除普伐他汀外的所有他汀类药物均增加了人平滑肌细胞中的t-PA产生。从摩尔浓度来看,西立伐他汀是最有效的HMG CoA还原酶抑制剂。仅辛伐他汀和洛伐他汀增加了内皮细胞中的t-PA产生。他汀类药物对纤维蛋白溶解系统的作用可被甲戊二酸逆转。他汀类药物降低了内皮细胞和平滑肌细胞中PAI-1的mRNA水平,并增加了平滑肌细胞中t-PA的mRNA水平。他汀类药物不影响HepG2细胞中的PAI-1表达。在内皮细胞和HepG2细胞中,他汀类药物不影响细胞活力,而在平滑肌细胞中,高浓度下观察到了细胞毒性作用。
如果本研究中血管细胞上他汀类药物对纤维蛋白溶解系统的作用在环境中同样适用,那么可以推测,通过在血管病变部位增加t-PA并减少PAI-1,他汀类药物可能会减少纤维蛋白形成和血栓的发展。这种效果可能有助于解释他汀类药物临床证实的益处。
British Journal of Pharmacology (2002) 135, 284–292; doi:10.1038/sj.bjp.0704454