Martinet Wim, Croons Valerie, Herman Arnold G, De Meyer Guido R Y
Division of Pharmacology, University of Antwerp, Antwerp, Wilrijk, Belgium.
Ann N Y Acad Sci. 2009 Aug;1171:365-71. doi: 10.1111/j.1749-6632.2009.04685.x.
Unstable atherosclerotic plaques are characterized by a thin fibrous cap that contains few smooth muscle cells (SMCs) and numerous foam cells of macrophage origin. Previously we and others demonstrated that macrophages disappear from atherosclerotic plaques after dietary lipid lowering. However, it remains unclear whether loss of macrophages after lipid lowering occurs via increased apoptosis, decreased macrophage replication and/or recruitment, or via a combination of both. Rabbits were fed a diet supplemented with cholesterol (0.3%) for 24 weeks followed by a normal diet for 4, 12, or 24 weeks. After 24 weeks of cholesterol supplement, plaques showed apoptosis in both macrophages and SMCs, as determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling. Cell replication (Ki-67 immunolabeling) was predominantly present in macrophages. After 24 weeks of cholesterol withdrawal, the thickness and areas of the plaques were unchanged. Nevertheless, plaques showed a considerable loss of macrophages. This event was associated with a reduced immunoreactivity for vascular cell adhesion molecule-1 (VCAM-1) in the endothelial cells starting 4 weeks after cholesterol withdrawal. Apoptosis did not increase after lipid lowering but showed a steady decline. Apart from decreased VCAM-1 expression, a strong decrease in Ki-67 immunolabeling was observed after 12 weeks of cholesterol withdrawal. Our findings suggest that loss of macrophages in atherosclerotic plaques after dietary lipid lowering is not related to induction of macrophage apoptosis but mainly a consequence of impaired monocyte recruitment followed by decreased macrophage replication. This information is essential for understanding the effects of aggressive lipid lowering on plaque stability.
不稳定动脉粥样硬化斑块的特征是纤维帽薄，其中平滑肌细胞（SMC）数量少，且有大量巨噬细胞源性泡沫细胞。此前我们和其他人证明，饮食降低血脂后巨噬细胞会从动脉粥样硬化斑块中消失。然而，目前尚不清楚血脂降低后巨噬细胞的减少是通过增加细胞凋亡、减少巨噬细胞复制和/或募集，还是两者兼而有之。给兔子喂食补充胆固醇（0.3%）的饲料24周，然后喂食正常饲料4周、12周或24周。补充胆固醇24周后，通过末端脱氧核苷酸转移酶dUTP缺口末端标记法测定，斑块中巨噬细胞和SMC均出现凋亡。细胞复制（Ki-67免疫标记）主要存在于巨噬细胞中。胆固醇撤去24周后，斑块的厚度和面积没有变化。然而，斑块中巨噬细胞大量减少。这一现象与胆固醇撤去4周后内皮细胞中血管细胞黏附分子-1（VCAM-1）的免疫反应性降低有关。血脂降低后细胞凋亡并未增加，而是呈稳步下降。除了VCAM-1表达降低外，胆固醇撤去12周后，Ki-67免疫标记也显著降低。我们的研究结果表明，饮食降低血脂后动脉粥样硬化斑块中巨噬细胞的减少与巨噬细胞凋亡的诱导无关，主要是单核细胞募集受损继而巨噬细胞复制减少的结果。这一信息对于理解积极降脂对斑块稳定性的影响至关重要。
