Aspirin Extrusion From Human Platelets Through Multidrug Resistance Protein-4-Mediated Transport Evidence of a Reduced Drug Action in Patients After Coronary Artery Bypass Grafting
Aspirin Extrusion From Human Platelets Through Multidrug Resistance Protein-4-Mediated Transport Evidence of a Reduced Drug Action in Patients After Coronary Artery Bypass Grafting
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DOI：
10.1016/j.jacc.2011.03.049
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发表时间：
2011-08-09
影响因子：
24
通讯作者：
Pulcinelli, Fabio M.
中科院分区：
文献类型：
--
作者：
Mattiello, Teresa;Guerriero, Raffaella;Pulcinelli, Fabio M.
目的：1）多药耐药蛋白4（multidrug resistance protein-4，MRP 4）是一种有机阴离子单向转运蛋白，它对阿司匹林对人血小板环氧化酶（cyclooxygenase，考克斯）-1的调节作用;以及2）在冠状动脉旁路移植术（CABG）患者中发现的阿司匹林-COX-1相互作用的损害，CABG患者的血小板对阿司匹林的敏感性降低，尽管在体内和体外药物治疗。阿司匹林是一种有机阴离子，可能是MRP 4的底物。方法采用凝血酶诱导的血栓素B2（TxB 2）产生法，测定了健康志愿者（HV）血小板和减少或不减少MRP 4转运的造血祖细胞培养物中细胞内阿司匹林浓度和药物考克斯1活性。在HV和CABG患者的血小板中评价血小板MRP 4表达，结果双嘧达莫或MK-571抑制MRP 4介导的转运可增加阿司匹林的包封率及其对考克斯-1活性的影响（142.7 +/- 34.6 pg/10（8）个细胞对比343.7 +/- 169.3 pg/10（8）个细胞TxB 2-产生）。经MRP 4小干扰核糖核酸转染的巨核细胞衍生的血小板具有较高的阿司匹林包封率和药物考克斯-1活性。CABG患者血小板高表达MRP 4，体外抑制阿司匹林对考克斯-1的抑制作用（349 ± 141 pg/10（8）cells vs. 1，670 ± 646 pg/10（8）cells TxB 2-production）。阿司匹林对考克斯-1的作用与MRP 4介导的阿司匹林在HV中的转运关系不大，但在MRP 4过表达的CABG患者中，其药理学抑制以有效的方式增强阿司匹林的作用。（J Am科尔心脏病学杂志2011;58：752-61）（C）美国心脏病学会基金会2011年
Objectives In this study we investigate: 1) the role of multidrug resistance protein-4 (MRP4), an organic anion unidirectional transporter, in modulating aspirin action on human platelet cyclooxygenase (COX)-1; and 2) whether the impairment of aspirin-COX-1 interaction, found in coronary artery bypass grafting (CABG) patients, could be dependent on MRP4-mediated transport.Background Platelets of CABG patients present a reduced sensitivity to aspirin despite in vivo and in vitro drug treatment. Aspirin is an organic anion and could be a substrate for MRP4.Methods Intracellular aspirin concentration and drug COX-1 activity, measured by thrombin-induced thromboxane B2 (TxB2) production, were evaluated in platelets obtained from healthy volunteers (HV) and hematopoietic-progenitor cell cultures reducing or not reducing MRP4-mediated transport. Platelet MRP4 expression was evaluated, in platelets from HV and CABG patients, by dot-blot or by immunogold-electromicrographs or immunofluorescence-microscopy analysis.Results Inhibition of MRP4-mediated transport by dipyridamole or Mk-571 increases aspirin entrapment and its in vitro effect on COX-1 activity (142.7 +/- 34.6 pg/10(8) cells vs. 343.7 +/- 169.3 pg/10(8) cells TxB2-production). Platelets derived from megakaryocytes transfected with MRP4 small interfering ribonucleic acid have a higher aspirin entrapment and drug COX-1 activity. Platelets from CABG patients showed a high expression of MRP4 whose in vitro inhibition enhanced aspirin effect on COX-1 (349 +/- 141 pg/10(8) cells vs. 1,670 +/- 646 pg/10(8) cells TxB2-production).Conclusions Aspirin is a substrate for MRP4 and can be extruded from platelet through its transportation. Aspirin effect on COX-1 is little-related to MRP4-mediated aspirin transport in HV, but in CABG patients with MRP4 over-expression, its pharmacological inhibition enhances aspirin action in an efficient way. (J Am Coll Cardiol 2011;58:752-61) (C) 2011 by the American College of Cardiology Foundation