Deficiency of inflammatory cell adhesion molecules protects against atherosclerosis in mice
Deficiency of inflammatory cell adhesion molecules protects against atherosclerosis in mice
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DOI：
10.1161/01.atv.17.8.1517
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发表时间：
1997-08-01
影响因子：
8.7
通讯作者：
Beaudet, AL
中科院分区：
文献类型：
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作者：
Nageh, MF;Sandberg, ET;Beaudet, AL
白细胞和内皮细胞粘附分子（CAM）对于白细胞的移出是必需的，其中选择素介导白细胞“滚动"的初始步骤，而β（2）-（CD 18）整联蛋白和细胞间粘附分子-1（ICAM-1）对于牢固粘附和移出是重要的。在动脉粥样硬化发病机制中炎症成分的证据的基础上，包括CAM、细胞因子和生长因子的表达增加，我们检验了炎性CAM表达减少将降低动脉粥样硬化易感性的假设。使用喂食高脂饮食的C57 BL/6小鼠，我们观察到ICAM-1、P-选择素、CD 18、ICAM-1和CD 18或ICAM-1和P-选择素均纯合突变的小鼠动脉粥样硬化脂肪条纹减少50%至75%。与先前在动脉粥样硬化病变中CAM表达增加的证据（其不能证明因果关系）相反，这些数据直接表明CAM的表达水平可以决定动脉粥样硬化脂肪条纹形成的易感性。结果表明，在这些位点的遗传变异可能会影响动脉粥样硬化的易感性和药理学减少这些CAM的表达或功能可能会防止动脉粥样硬化。
Leukocyte and endothelial cell adhesion molecules (CAMs) are essential for emigration of leukocytes, with the selectins mediating the initial step of leukocyte ''rolling'' and the beta(2)-(CD18) integrins and intercellular adhesion molecule-1 (ICAM-1) being important for firm adhesion and emigration. On the basis of evidence for an inflammatory component in the pathogenesis of atherosclerosis, including increased expression of CAMs, cytokines, and growth factors, we tested the hypothesis that decreased expression of inflammatory CAMs would reduce susceptibility to atherosclerosis. Using C57BL/6 mice fed a high-fat diet, we observed a 50% to 75% reduction in atherosclerotic fatty streaks in mice with homozygous mutations for ICAM-1, P-selectin, CD18, both ICAM-1 and CD18, or both ICAM-1 and P-selectin. In contrast to previous evidence of increased expression of CAMs in atherosclerotic lesions, which does not prove a cause-and-effect relationship, these data indicate directly that the level of expression of CAMs can determine the susceptibility to the formation of atherosclerotic fatty streaks. The results suggest that genetic variation at these loci could influence susceptibility to atherosclerosis and that pharmacological reduction of the expression or function of these CAMs might protect against atherosclerosis.