Prominent role of P-selectin in the development of advanced atherosclerosis in apoE-deficient mice
Prominent role of P-selectin in the development of advanced atherosclerosis in apoE-deficient mice
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DOI：
10.1161/01.cir.101.19.2290
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发表时间：
2000-05-16
期刊：
影响因子：
37.8
通讯作者：
Wagner, DD
中科院分区：
文献类型：
--
作者：
Dong, ZM;Brown, AA;Wagner, DD
背景：白细胞和内皮细胞之间的粘附相互作用是动脉粥样硬化病变发展的特征，但涉及的受体仍未确定。p -选择素是一种粘附受体，在活化的内皮细胞或血小板上表达，并被证明参与了低密度脂蛋白受体缺乏小鼠在致动脉粥样硬化饮食中的脂肪条纹形成。本研究的主要目的是研究p -选择素在apoe缺陷小鼠晚期动脉粥样硬化自发发展中的规律。方法与结果：我们将P-选择素缺失小鼠与apoE缺失小鼠杂交，比较apoE缺失小鼠在正常小鼠饲料中添加P-选择素（apoE(-/-) P+/+）和不添加P-选择素（apoE(-/-) P-/-）的病变发展情况。在4月龄时，apoE(-/-) P-/-小鼠的主动脉窦病变比apoE(-/-) P+/+小鼠小3.5倍。这些仅限于apoE(-/-) P-/-小鼠的脂肪条纹，而70%的apoE(-/-) P+/+病变含有平滑肌细胞。在apoE(-/-) P+/+的动物中，病变覆盖的主动脉窦周长明显更多。p -选择素基因型影响巨噬细胞募集，因为在p -选择素阳性病变中存在两倍多的单核细胞。15个月时，两种基因型的病变进展为纤维斑块阶段，并扩散到整个主动脉，但apoE(-/-) P-/-小鼠的这一过程延迟。在主动脉窦，apoE(-/-) P-/-小鼠的病变小2.6倍，钙化程度较低。结论- p -选择素可能是apoe缺陷小鼠中介导白细胞向病变聚集并促进晚期动脉粥样硬化的关键粘附受体。
Background-Adhesive interactions between leukocytes and endothelial cells are characteristic or the development of atherosclerotic lesions, but the receptors involved remain to be defined. P-selectin is an adhesion receptor expressed on activated endothelial cells or platelets and was shown to be involved in fatty streak formation in LDL receptor-deficient mice on an atherogenic diet. The main purpose of this study is to examine the rule of P-selectin in the spontaneous development of advanced atherosclerosis in apoE-deficient mice.Methods and Results-We intercrossed P-selectin-deficient mice with mice lacking apoE and compared lesion development in apoE-deficient mice with P-selectin (apoE(-/-) P+/+) and without P-selectin (apoE(-/-) P-/-) that were fed normal mouse chow. At 4 months of age, apoE(-/-) P-/- mice had 3.5-fold smaller aortic sinus lesions than apoE(-/-) P+/+ mice. These were limited to fatty streaks in the apoE(-/-) P-/- mice, whereas 70% of apoE(-/-) P+/+ lesions contained smooth muscle cells. Significantly more of the aortic sinus circumference was covered by lesions in the apoE(-/-) P+/+ animals. The P-selectin genotype affected macrophage recruitment, because twice as many mononuclear cells were present in the P-selectin-positive lesions. At 15 months, the lesions progressed to the fibrous plaque stage in both genotypes and spread throughout the aorta, but this process was delayed in apoE(-/-) P-/- mice. In the aortic sinus, the lesions of the apoE(-/-) P-/- mice were 2.6-fold smaller and less calcified.Conclusions-P-selectin appears to be a key adhesion receptor mediating leukocyte recruitment into lesions and promoting advanced atherosclerosis in apoE-deficient mice.