Dong Z M, Chapman S M, Brown A A, Frenette P S, Hynes R O, Wagner D D
Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Clin Invest. 1998 Jul 1;102(1):145-52. doi: 10.1172/JCI3001.
P- and E-selectins are adhesion molecules mediating the first step in leukocyte extravasation. Because their function in leukocyte adhesion is overlapping, we hypothesized that there might be a combined effect of these selectins on the development of atherosclerotic lesions. We bred P- and E-selectin-double-deficient mice onto the low-density lipoprotein receptor (LDLR)-deficient background (LDLR-/- P/E-/-) and compared lesion development in these mice to that in mice wild type for both selectins (LDLR-/- P/E+/+). After 8 wk on atherogenic diet, the LDLR-/- P/E-/- mice developed fatty streaks in the aortic sinus that were five times smaller than those in LDLR-/- P/E+/+ mice. The density of macrophages in the fatty streaks was comparable between LDLR-/- P/E+/+ and LDLR-/- P/E-/- mice. After 22 wk on the diet, the lesions spread throughout the aorta but this process was delayed in LDLR-/- P/E-/- mice. At 37 wk on diet, the lesions progressed to the fibrous plaque stage in both genotypes. However, the lesions in the aortic sinus in LDLR-/- P/E-/- mice were 40% smaller and less calcified than those of LDLR-/- P/E +/+ mice. Our results suggest that P- and E-selectins together play an important role in both early and advanced stages of atherosclerotic lesion development.
P-选择素和E-选择素是介导白细胞渗出第一步的黏附分子。由于它们在白细胞黏附中的功能存在重叠，我们推测这些选择素可能对动脉粥样硬化病变的发展具有联合作用。我们将P-和E-选择素双缺陷小鼠培育到低密度脂蛋白受体（LDLR）缺陷背景（LDLR-/- P/E-/-）上，并将这些小鼠的病变发展与两种选择素均为野生型的小鼠（LDLR-/- P/E+/+）进行比较。在致动脉粥样硬化饮食8周后，LDLR-/- P/E-/-小鼠在主动脉窦中形成的脂肪条纹比LDLR-/- P/E+/+小鼠小5倍。LDLR-/- P/E+/+和LDLR-/- P/E-/-小鼠脂肪条纹中的巨噬细胞密度相当。饮食22周后，病变扩散至整个主动脉，但这一过程在LDLR-/- P/E-/-小鼠中延迟。饮食37周时，两种基因型的病变均进展至纤维斑块阶段。然而，LDLR-/- P/E-/-小鼠主动脉窦中的病变比LDLR-/- P/E+/+小鼠小40%，且钙化程度更低。我们的结果表明，P-选择素和E-选择素共同在动脉粥样硬化病变发展的早期和晚期阶段发挥重要作用。
