通过抑制HMG-CoA还原酶逆转凝血酶诱导的内皮细胞CD39/ atpase失活:对Rho-GTPase和腺苷核苷酸代谢的影响

N. Kaneider, P. Egger, S. Dunzendorfer, P. Noris, C. Balduini, D. Gritti, G. Ricevuti, C. Wiedermann
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引用次数: 46

摘要

激活血小板、白细胞和内皮功能的三磷酸腺苷和二磷酸腺苷被内皮细胞CD39/ atpase水解。由于内皮细胞中的CD39/ atpase在炎症中下调,这可能受到HMG-CoA还原酶抑制剂的影响,我们研究了西伐他汀和辛伐他汀在调节内皮细胞CD39/ atpase表达、ATP/ADP代谢和血小板功能中的作用。用他汀类药物处理体外凝血酶刺激的内皮细胞,用高效液相色谱法和孔雀石绿法检测外源性ADP和ATP的水解情况。血小板聚集研究以内皮细胞上清液为触发物。内皮细胞CD39/ atpase表面表达采用荧光活化细胞分选仪,mRNA表达采用RT-PCR, rho - gtpase的凝集酶诱导解离采用Western blotting。辛伐他汀或西伐他汀治疗可通过防止凝血酶诱导的CD39/ atpase下调,恢复凝血酶激活的内皮细胞外源性ATP和ADP代谢受损。在血小板聚集研究中,凝血酶激活的内皮细胞的ATP和ADP上清液在他汀类药物存在时比在他汀类药物不存在时刺激更小。数据显示,他汀类药物可维持凝血酶处理的内皮细胞中CD39/ atpase活性,这涉及到他汀类药物对Rho-GTPase功能和CD39/ atpase表达的改变。保留腺嘌呤核苷酸代谢可能直接有助于观察到他汀类药物的抗血栓和抗炎作用。
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Reversal of Thrombin-Induced Deactivation of CD39/ATPDase in Endothelial Cells by HMG-CoA Reductase Inhibition: Effects on Rho-GTPase and Adenosine Nucleotide Metabolism
Adenosine triphosphate and diphosphate that activate platelet, leukocyte, and endothelium functions are hydrolyzed by endothelial CD39/ATPDase. Because CD39/ATPDase is downregulated in endothelial cells by inflammation and this may be affected by HMG-CoA reductase inhibitors, we examined the role of cerivastatin and simvastatin in regulation of endothelial CD39/ATPDase expression, metabolism of ATP/ADP, and function in platelets. Thrombin-stimulated endothelial cells in vitro were treated with the statins, and hydrolysis of exogenous ADP and ATP was assessed by high-performance liquid chromatography and malachite green assay. Platelet aggregation studies were performed with endothelial cell supernatants as triggers. CD39/ATPDase surface expression by endothelial cells was determined immunologically by fluorescence-activated cell sorter, mRNA expression by RT-PCR, and thrombin-induced dissociation of Rho-GTPases by Western blotting. Treatment by simvastatin or cerivastatin restored impaired metabolism of exogenous ATP and ADP in thrombin-activated endothelial cells by preventing thrombin-induced downregulation of CD39/ATPDase. In platelet aggregation studies, ATP and ADP supernatants of thrombin-activated endothelial cells were less stimulatory in the presence of statins than in their absence. Data show that statins preserve CD39/ATPDase activity in thrombin-treated endothelial cells involving alterations by statins of Rho-GTPase function and CD39/ATPDase expression. Preservation of adenine nucleotide metabolism may directly contribute to the observed anti-thrombotic and anti-inflammatory actions of statins.
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