Endothelial cell PECAM-1 promotes atherosclerotic lesions in areas of disturbed flow in ApoE-deficient mice.
Endothelial cell PECAM-1 promotes atherosclerotic lesions in areas of disturbed flow in ApoE-deficient mice.
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DOI：
10.1161/atvbaha.108.164707
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发表时间：
2008-11
期刊：
影响因子：
--
通讯作者：
Ley K
中科院分区：
文献类型：
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作者：
Harry BL;Sanders JM;Feaver RE;Lansey M;Deem TL;Zarbock A;Bruce AC;Pryor AW;Gelfand BD;Blackman BR;Schwartz MA;Ley K
血小板内皮细胞粘附分子-1（PECAM-1，CD31）最近被证明是介导内皮对流体剪切应力反应的机械感觉复合物的基本元素。本研究的目的是确定 PECAM-1 在动脉粥样硬化中的体内作用。我们将 C57BL/6 Pecam1−/− 小鼠与载脂蛋白 E 缺陷 (Apoe−/−) 小鼠进行杂交。在西方饮食中，与 Apoe−/− 小鼠相比，Pecam1−/−Apoe−/− 小鼠的动脉粥样硬化病变尺寸减小。在主动脉弓小弯处观察到了显着的差异，这是一个血流紊乱的区域，但在降胸主动脉或腹主动脉中却没有观察到。 Pecam1−/−Apoe−/− 小鼠中血管细胞粘附分子-1 (VCAM-1) 表达、巨噬细胞浸润和内皮核 NF-κB 均减少。骨髓移植表明内皮PECAM-1是主动脉弓动脉粥样硬化的主要决定因素，但造血PECAM-1促进腹主动脉病变。体外数据表明，基于 siRNA 的 PECAM-1 敲低可减弱动脉粥样硬化血流条件下的内皮 NF-κB 活性和 VCAM-1 表达。这些结果表明，内皮 PECAM-1 通过调节 NF-κB 介导的基因表达，促进血流紊乱区域动脉粥样硬化病变的形成。
Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) has recently been shown to form an essential element of a mechanosensory complex that mediates endothelial responses to fluid shear stress. The aim of this study was to determine the in vivo role of PECAM-1 in atherosclerosis. We crossed C57BL/6 Pecam1−/− mice with apolipoprotein E–deficient (Apoe−/−) mice. On a Western diet, Pecam1−/−Apoe−/− mice showed reduced atherosclerotic lesion size compared to Apoe−/− mice. Striking differences were observed in the lesser curvature of the aortic arch, an area of disturbed flow, but not in the descending thoracic or abdominal aorta. Vascular cell adhesion molecule-1 (VCAM-1) expression, macrophage infiltration, and endothelial nuclear NF-κB were all reduced in Pecam1−/−Apoe−/− mice. Bone marrow transplantation suggested that endothelial PECAM-1 is the main determinant of atherosclerosis in the aortic arch, but that hematopoietic PECAM-1 promotes lesions in the abdominal aorta. In vitro data show that siRNA-based knockdown of PECAM-1 attenuates endothelial NF-κB activity and VCAM-1 expression under conditions of atheroprone flow. These results indicate that endothelial PECAM-1 contributes to atherosclerotic lesion formation in regions of disturbed flow by regulating NF-κB–mediated gene expression.