Yu Guangyao, Rux Ann H, Ma Peihong, Bdeir Khalil, Sachais Bruce S
University of Pennsylvania, 207 John Morgan, Philadelphia, PA 19104, USA.
Blood. 2005 May 1;105(9):3545-51. doi: 10.1182/blood-2004-07-2617. Epub 2004 Dec 9.
The involvement of platelets in the pathogenesis of atherosclerosis has recently gained much attention. Platelet factor 4 (PF4), a platelet-specific chemokine released on platelet activation, has been localized to atherosclerotic lesions, including macrophages and endothelium. In this report, we demonstrate that E-selectin, an adhesion molecule involved in atherogenesis, is up-regulated in human umbilical vein endothelial cells exposed to PF4. Induction of E-selectin RNA is time and dose dependent. Surface expression of E-selectin, as measured by flow cytometry, is also increased by PF4. PF4 induces E-selectin expression by activation of transcriptional activity. Activation of nuclear factor-kappaB is critical for PF4-induced E-selectin expression, as demonstrated by promoter activation studies and electrophoretic mobility shift assays. Further, we have identified the low-density lipoprotein receptor-related protein as the cell surface receptor mediating this effect. These results demonstrate that PF4 is able to increase expression of E-selectin by endothelial cells and represents another potential mechanism by which platelets may participate in atherosclerotic lesion progression.
血小板在动脉粥样硬化发病机制中的作用近来备受关注。血小板因子4(PF4)是血小板活化时释放的一种血小板特异性趋化因子,已定位到动脉粥样硬化病变处,包括巨噬细胞和内皮细胞。在本报告中,我们证明参与动脉粥样硬化形成的黏附分子E-选择素,在暴露于PF4的人脐静脉内皮细胞中上调。E-选择素RNA的诱导呈时间和剂量依赖性。通过流式细胞术检测,PF4也增加了E-选择素的表面表达。PF4通过激活转录活性诱导E-选择素表达。如启动子激活研究和电泳迁移率变动分析所示,核因子-κB的激活对PF4诱导的E-选择素表达至关重要。此外,我们已确定低密度脂蛋白受体相关蛋白为介导此效应的细胞表面受体。这些结果表明,PF4能够增加内皮细胞中E-选择素的表达,代表了血小板可能参与动脉粥样硬化病变进展的另一种潜在机制。