Macrophage Phospholipid Transfer Protein Contributes Significantly to Total Plasma Phospholipid Transfer Activity and Its Deficiency Leads to Diminished Atherosclerotic Lesion Development
Macrophage Phospholipid Transfer Protein Contributes Significantly to Total Plasma Phospholipid Transfer Activity and Its Deficiency Leads to Diminished Atherosclerotic Lesion Development
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DOI：
10.1161/01.atv.0000254815.49414.be
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发表时间：
2007-03
期刊：
影响因子：
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通讯作者：
R. Vikstedt;D. Ye;J. Metso;Reeni B. Hildebrand;T. V. van Berkel;C. Ehnholm;M. Jauhiainen;M. Van Eck
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文献类型：
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作者：
R. Vikstedt;D. Ye;J. Metso;Reeni B. Hildebrand;T. V. van Berkel;C. Ehnholm;M. Jauhiainen;M. Van Eck
目的：小鼠体内系统性磷脂转移蛋白（PLTP）缺乏与动脉粥样硬化易感性降低有关，而小鼠体内人类PLTP的过度表达会增加动脉粥样硬化病变的发展。在人类动脉粥样硬化病变中，巨噬细胞衍生的泡沫细胞也表达PLTP，但巨噬细胞PLTP在动脉粥样硬化中的确切作用尚不清楚。方法和结果：为了明确巨噬细胞PLTP在动脉粥样硬化中的作用，通过将PLTP敲除（PLTP−/−）小鼠的骨髓移植到辐照的低密度脂蛋白受体敲除小鼠中，选择性地破坏了包括巨噬细胞在内的造血细胞中的PLTP。巨噬细胞PLTP （PLTP−M/−M）选择性缺乏导致主动脉根部病变面积与具有功能巨噬细胞PLTP的小鼠相比减少29%（病变面积差异P<0.01） (PLTP−M/−M组为384±36*103 m2 （n=10)，而PLTP+M/+M组为539±35*103 m2 (n=14)）。在PLTP - M/ - M组中，病变大小的减小与这些小鼠血清总胆固醇、游离胆固醇和甘油三酯水平的显著降低相一致。此外，PLTP−M/−M组的血浆PLTP活性比PLTP+M/+M组低2倍（P<0.001）。结论：巨噬细胞PLTP是影响血浆PLTP活性的重要因素，巨噬细胞PLTP缺乏可降低低密度脂蛋白受体敲除小鼠的动脉粥样硬化病变发展。
Objective—Systemic phospholipid transfer protein (PLTP) deficiency in mice is associated with a decreased susceptibility to atherosclerosis, whereas overexpression of human PLTP in mice increases atherosclerotic lesion development. PLTP is also expressed by macrophage-derived foam cells in human atherosclerotic lesions, but the exact role of macrophage PLTP in atherosclerosis is unknown. Methods and Results—To clarify the role of macrophage PLTP in atherogenesis, PLTP was selectively disrupted in hematopoietic cells, including macrophages, by transplantation of bone marrow from PLTP knockout (PLTP−/−) mice into irradiated low-density lipoprotein receptor knockout mice. Selective deficiency of macrophage PLTP (PLTP−M/−M) resulted in a 29% (P<0.01 for difference in lesion area) reduction in aortic root lesion area as compared with mice possessing functional macrophage PLTP (384±36*103 m2 in the PLTP−M/−M group (n=10), as compared with 539±35*103 m2 in the PLTP+M/+M group (n=14)) after 9 weeks of Western-type diet feeding. The decreased lesion size in the PLTP−M/−M group coincided with significantly lower serum total cholesterol, free cholesterol, and triglyceride levels in these mice. Furthermore, plasma PLTP activity in the PLTP−M/−M group was 2-fold (P<0.001) lower than that in the PLTP+M/+M group. Conclusion—Macrophage PLTP is a significant contributor to plasma PLTP activity and deficiency of PLTP in macrophages leads to lowered atherosclerotic lesion development in low-density lipoprotein receptor knockout mice on Western-type diet.