van Haperen Rien, Samyn Hannelore, Moerland Matthijs, van Gent Teus, Peeters Marian, Grosveld Frank, van Tol Arie, de Crom Rini
Department of Cell Biology and Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
PLoS One. 2008 May 28;3(5):e2255. doi: 10.1371/journal.pone.0002255.
Phospholipid transfer protein (PLTP) is expressed by various cell types. In plasma, it is associated with high density lipoproteins (HDL). Elevated levels of PLTP in transgenic mice result in decreased HDL and increased atherosclerosis. PLTP is present in human atherosclerotic lesions, where it seems to be macrophage derived. The aim of the present study is to evaluate the atherogenic potential of macrophage derived PLTP.
Here we show that macrophages from human PLTP transgenic mice secrete active PLTP. Subsequently, we performed bone marrow transplantations using either wild type mice (PLTPwt/wt), hemizygous PLTP transgenic mice (huPLTPtg/wt) or homozygous PLTP transgenic mice (huPLTPtg/tg) as donors and low density lipoprotein receptor deficient mice (LDLR-/-) as acceptors, in order to establish the role of PLTP expressed by bone marrow derived cells in diet-induced atherogenesis. Atherosclerosis was increased in the huPLTPtg/wt-->LDLR-/- mice (2.3-fold) and even further in the huPLTPtg/tg-->LDLR-/- mice (4.5-fold) compared with the control PLTPwt/wt-->LDLR-/- mice (both P<0.001). Plasma PLTP activity levels and non-HDL cholesterol were increased and HDL cholesterol decreased compared with controls (all P<0.01). PLTP was present in atherosclerotic plaques in the mice as demonstrated by immunohistochemistry and appears to co-localize with macrophages. Isolated macrophages from PLTP transgenic mice do not show differences in cholesterol efflux or in cytokine production. Lipopolysaccharide activation of macrophages results in increased production of PLTP. This effect was strongly amplified in PLTP transgenic macrophages.
We conclude that PLTP expression by bone marrow derived cells results in atherogenic effects on plasma lipids, increased PLTP activity, high local PLTP protein levels in the atherosclerotic lesions and increased atherosclerotic lesion size.
磷脂转运蛋白（PLTP）由多种细胞类型表达。在血浆中，它与高密度脂蛋白（HDL）相关。转基因小鼠中PLTP水平升高导致HDL降低和动脉粥样硬化增加。PLTP存在于人类动脉粥样硬化病变中，似乎源自巨噬细胞。本研究的目的是评估巨噬细胞衍生的PLTP的致动脉粥样硬化潜力。
我们在此表明，来自人PLTP转基因小鼠的巨噬细胞分泌活性PLTP。随后，我们使用野生型小鼠（PLTPwt/wt）、半合子PLTP转基因小鼠（huPLTPtg/wt）或纯合子PLTP转基因小鼠（huPLTPtg/tg）作为供体，低密度脂蛋白受体缺陷小鼠（LDLR-/-）作为受体进行骨髓移植，以确定骨髓来源细胞表达的PLTP在饮食诱导的动脉粥样硬化中的作用。与对照PLTPwt/wt-->LDLR-/-小鼠相比，huPLTPtg/wt-->LDLR-/-小鼠的动脉粥样硬化增加了2.3倍，在huPLTPtg/tg-->LDLR-/-小鼠中甚至进一步增加了4.5倍（两者P<0.001）。与对照组相比，血浆PLTP活性水平和非HDL胆固醇增加，HDL胆固醇降低（所有P<0.01）。免疫组织化学证明PLTP存在于小鼠的动脉粥样硬化斑块中，并且似乎与巨噬细胞共定位。来自PLTP转基因小鼠的分离巨噬细胞在胆固醇流出或细胞因子产生方面没有差异。巨噬细胞的脂多糖激活导致PLTP产生增加。这种效应在PLTP转基因巨噬细胞中被强烈放大。
我们得出结论，骨髓来源细胞表达的PLTP对血浆脂质产生致动脉粥样硬化作用，增加PLTP活性，动脉粥样硬化病变中局部PLTP蛋白水平升高，以及动脉粥样硬化病变大小增加。
