Dunzendorfer S, Rothbucher D, Schratzberger P, Reinisch N, Kähler C M, Wiedermann C J
Department of Internal Medicine, University of Innsbruck, Austria.
Circ Res. 1997 Dec;81(6):963-9. doi: 10.1161/01.res.81.6.963.
Pravastatin, a hydrophilic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, has been reported to beneficially affect atherogenesis, plaque stability, and transient myocardial ischemia in significant coronary artery disease by influencing lipid metabolism and by intracellular signaling via mevalonate pathway products other than cholesterol. Leukocytes are implicated to play a pathophysiological role in these events. We were interested in finding out whether pravastatin could affect transendothelial migration (TEM), chemotaxis, and respiratory burst activity of the neutrophil ex vivo. In addition, effects on monocyte and T-lymphocyte chemotaxis were tested. For TEM assays, monolayers of human umbilical vein endothelial cells (HUVECs) were grown to confluence on polycarbonate filters bearing 5-microns pores in Transwell (Costar) culture plate inserts. Chemotaxis experiments were performed using modified Boyden chambers with cellulose nitrate micropore filters. Respiratory burst activity was measured fluorometrically. Treatment of neutrophils and monocytes with pravastatin at 2 to 200 mumol/L and 10 to 1000 mumol/L, respectively, significantly decreased chemotaxis triggered by fMet-Leu-Phe. This effect was abolished in the presence of mevalonic acid (500 mumol/L); no effect of pravastatin was seen on T-lymphocyte chemotaxis triggered by interleukin-8. Preincubation of neutrophils with pravastatin (200 mumol/L) also resulted in a significant reduction in the number of neutrophils that transmigrated a tumor necrosis factor-stimulated or lipopolysaccharide-stimulated HUVEC monolayer. At none of the concentrations tested (2 pmol/L to 200 mumol/L) did pravastatin affect neutrophil respiratory burst activity. We conclude that pravastatin may alter monocyte chemotaxis and neutrophil-endothelial interactions in migratory responses at concentrations obtained in vivo with cholesterol-lowering doses.
普伐他汀是一种亲水性3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，据报道，它可通过影响脂质代谢以及通过甲羟戊酸途径产物（而非胆固醇）的细胞内信号传导，对严重冠状动脉疾病的动脉粥样硬化形成、斑块稳定性和短暂性心肌缺血产生有益影响。白细胞被认为在这些事件中发挥病理生理作用。我们感兴趣的是，普伐他汀是否能在体外影响中性粒细胞的跨内皮迁移（TEM）、趋化性和呼吸爆发活性。此外，还测试了对单核细胞和T淋巴细胞趋化性的影响。对于TEM测定，将人脐静脉内皮细胞（HUVECs）单层培养至在Transwell（Costar）培养板插入物中带有5微米孔的聚碳酸酯滤膜上汇合。趋化性实验使用带有硝酸纤维素微孔滤膜的改良博伊登小室进行。呼吸爆发活性通过荧光法测量。分别用2至200μmol/L和10至1000μmol/L的普伐他汀处理中性粒细胞和单核细胞，可显著降低由fMet-Leu-Phe触发的趋化性。在甲羟戊酸（500μmol/L）存在的情况下，这种作用被消除；普伐他汀对白细胞介素-8触发的T淋巴细胞趋化性没有影响。用普伐他汀（200μmol/L）预孵育中性粒细胞也导致迁移通过肿瘤坏死因子刺激或脂多糖刺激的HUVEC单层的中性粒细胞数量显著减少。在所测试的任何浓度（2pmol/L至200μmol/L）下，普伐他汀均未影响中性粒细胞的呼吸爆发活性。我们得出结论，普伐他汀可能在体内降低胆固醇剂量所达到的浓度下，改变单核细胞趋化性和中性粒细胞与内皮细胞在迁移反应中的相互作用。
