Kaneider Nicole C, Egger Petra, Dunzendorfer Stefan, Wiedermann Christian J
Division of General Internal Medicine, Department of Internal Medicine, University of Innsbruck, Innsbruck, Austria.
Arterioscler Thromb Vasc Biol. 2002 Jun 1;22(6):1029-35. doi: 10.1161/01.atv.0000018306.68268.86.
Platelet activation and aggregation is considered a crucial step in the initiation and aggravation of arterial thrombosis. ADP from activated platelets is recognized as major factor in thrombus formation and is a potent stimulator of oxygen-free radical release from neutrophils. The aim of the present investigation was to determine in vitro the direct effects of statins on ATP and ADP secretion by platelets and its impact on subsequent oxidative burst activity in neutrophils. Human neutrophils and platelets were isolated from peripheral blood. Levels of platelet-derived ATP and ADP were measured by high-performance liquid chromatography, oxygen-free radical release of neutrophils was measured fluorometrically, and chemotaxis experiments were performed. Rho-GTPases were studied by Western blot analysis. Thrombin-activated platelets primed neutrophils for enhanced oxygen-free radical release on triggering with formyl-Met-Leu-Phe, reduced by cerivastatin and simvastatin treatment of platelets. The two statins decreased the amount of adenosine-derivative release in these cells. Rho-GTPases, required for the thrombin signaling in platelets and neutrophils, were decreased after coincubation with statins. Data demonstrate that inhibition of Rho-GTPases by statins inhibit platelet ADP and ATP release and the consecutive augmentation of neutrophil oxygen-free radical release. Statins affect platelet-neutrophil interactions by altering Rho-GTPase-dependent adenosine nucleotide function.
血小板活化和聚集被认为是动脉血栓形成和加重过程中的关键步骤。活化血小板释放的二磷酸腺苷（ADP）被认为是血栓形成的主要因素，并且是中性粒细胞释放氧自由基的有效刺激物。本研究的目的是在体外确定他汀类药物对血小板ATP和ADP分泌的直接影响及其对随后中性粒细胞氧化爆发活性的影响。从外周血中分离出人中性粒细胞和血小板。通过高效液相色谱法测量血小板衍生的ATP和ADP水平，用荧光法测量中性粒细胞的氧自由基释放，并进行趋化性实验。通过蛋白质印迹分析研究Rho-GTP酶。凝血酶激活的血小板使中性粒细胞致敏，使其在受到甲酰-甲硫氨酰-亮氨酰-苯丙氨酸刺激时增强氧自由基释放，而辛伐他汀和西立伐他汀处理血小板可降低这种释放。这两种他汀类药物减少了这些细胞中腺苷衍生物的释放量。血小板和中性粒细胞中凝血酶信号传导所需的Rho-GTP酶在与他汀类药物共同孵育后减少。数据表明，他汀类药物对Rho-GTP酶的抑制作用可抑制血小板ADP和ATP的释放以及随后中性粒细胞氧自由基释放的增加。他汀类药物通过改变Rho-GTP酶依赖性腺苷核苷酸功能来影响血小板-中性粒细胞相互作用。
