Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis in low density lipoprotein receptor-deficient mice
Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis in low density lipoprotein receptor-deficient mice
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DOI：
10.1074/jbc.m002423200
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发表时间：
2000-08-25
影响因子：
4.8
通讯作者：
Linton, MF
中科院分区：
文献类型：
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作者：
Babaev, VR;Patel, MB;Linton, MF
在低密度脂蛋白受体（LDLR-/-）小鼠中，研究了巨噬细胞脂蛋白脂肪酶（LPL）表达在动脉粥样硬化病变形成中的作用，采用设计的饮食条件诱导脂肪条纹病变或复杂的动脉粥样硬化病变。首先，用LPL-/- (n = 12)或LPL+/+ (n = 14)胎肝细胞作为造血细胞来源，将经致死照射的雌性LDLR-/-小鼠移植成巨噬细胞表达LPL嵌合物。为了诱导脂肪条纹病变，给小鼠喂食西方饮食8周，导致严重的高胆固醇血症，两组之间血浆肝素后LPL活性、血清脂质水平和脂蛋白分布没有差异。LPL-/- --> LDLR-/-小鼠近端主动脉平均病变面积较LPL+/+ -> LDLR-/-小鼠显著减少33%，对主动脉进行表面分析发现，病变面积也有类似的减少（38%）。为了诱导复杂的动脉粥样硬化病变，对雌性LDLR-/-小鼠进行致死性照射，移植LPL-/-(n = 14)、LPL+/- (n = 13)、LPL+/+ (n = 14)胎肝细胞，饲喂西餐19周。血清胆固醇和甘油三酯水平在三组之间没有差异。饮食19周后，LPL+/+—> LDLR-/-小鼠近端主动脉病变复杂，表达LPL蛋白和mRNA的巨噬细胞相对较少。近端主动脉横断面分析显示各组间病变面积无差异，而主动脉表面分析显示巨噬细胞LPL对LPL-/- --> LDLR-/-、LPL-/+ -> LDLR-/-和LPL+/+ -> LDLR-/-小鼠的平均主动脉病变面积有剂量依赖性（分别为1.8 +/- 0.2%、3.5 +/- 0.5%和5.9 +/- 0.8%）。综上所述，这些数据表明，巨噬细胞LPL在动脉壁上的表达促进了泡沫细胞病变形成过程中的动脉粥样硬化，但这种影响可能仅限于富含巨噬细胞的病变。
The role of macrophage lipoprotein lipase (LPL) expression in atherosclerotic lesion formation was examined in low density lipoprotein receptor (LDLR-/-) mice using dietary conditions designed to induce either fatty streak lesions or complex atherosclerotic lesions. First, LDLR-/- mice chimeric for macrophage LPL expression were created by transplantation of lethally irradiated female LDLR-/- mice with LPL-/- (n = 12) or LPL+/+ (n = 14) fetal liver cells as a source of hematopoietic cells. To induce fatty streak lesions, these mice were fed a Western diet for 8 weeks, resulting in severe hypercholesterolemia, There were no differences in plasma postheparin LPL activity, serum lipid levels, or lipoprotein distribution between these two groups. The mean lesion area in the proximal aorta in LPL-/- --> LDLR-/- mice was significantly reduced by 33% compared with LPL+/+ --> LDLR-/- mice, and a similar reduction (38%) in lesion area was found by en face analysis of the aortae. To induce complex atherosclerotic lesions, female LDLR-/- mice were lethally irradiated, transplanted with LPL-/-(n = 14), LPL+/- (n = 13), or LPL+/+ (n = 14) fetal liver cells, and fed the Western diet for 19 weeks. Serum cholesterol and triglyceride levels did not differ between the three groups. After 19 weeks of diet, the lesions in the proximal aorta were complex with relatively few macrophages expressing LPL protein and mRNA in LPL+/+ --> LDLR-/- mice. Analysis of cross-sections of the proximal aorta demonstrated no differences in the extent of lesion area between the groups, whereas en face analysis of the aortae revealed a dose-dependent effect of macrophage LPL on mean aortic lesion area in LPL-/- --> LDLR-/-, LPL-/+ --> LDLR-/-, and LPL+/+ --> LDLR-/- mice (1.8 +/- 0,2%, 3.5 +/- 0.5% and 5.9 +/- 0,8%, respectively). Taken together, these data indicate that macrophage LPL expression in the artery wall promotes atherogenesis during foam cell lesion formation, but this impact may be limited to macrophage-rich lesions.