Sphingosine-1-phosphate analogue FTY720 causes lymphocyte redistribution and hypercholesterolemia in ApoE-deficient mice
Sphingosine-1-phosphate analogue FTY720 causes lymphocyte redistribution and hypercholesterolemia in ApoE-deficient mice
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DOI：
10.1161/atvbaha.107.149476
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发表时间：
2007-11-01
影响因子：
8.7
通讯作者：
Dengler, Thomas J.
中科院分区：
文献类型：
--
作者：
Klingenberg, Roland;Nofer, Jerzy-Roch;Dengler, Thomas J.
常驻免疫细胞是动脉粥样硬化病变的标志。鞘脂类似物药物FTY 720介导免疫细胞的再运输，并抑制它们归巢到炎症部位。我们已经评估了FTY 720对动脉粥样硬化和脂质代谢的影响。方法和结果ApoE（-/-）小鼠在正常的实验室饮食接受口服FTY 720 12周，导致血清胆固醇（主要是极低密度脂蛋白部分）增加2.4倍，肝HMGCoA还原酶mRNA增加1.8倍。FTY 720增加血浆鞘氨醇-1-磷酸，并诱导明显的外周血淋巴细胞减少症。外周淋巴器官中发现B、T和单核细胞数量的不协调调节。T细胞的总体消耗伴随着调节性T细胞含量的相对（2倍）增加，以及效应记忆T细胞（CD 4 + CD 44 hiCD 62 lo）的类似增加，因为两个亚群的绝对数量基本保持不变。淋巴细胞功能未改变，如抗OxLDL抗体和T细胞增殖所示。有没有变化，动脉粥样硬化病变在早期和建立atherosclerosis. Conclusions FTY 720介导的外周淋巴细胞耗竭和retrafficking没有改变功能和整体平衡的亲和抗动脉粥样硬化的淋巴细胞群体。淋巴细胞数量的净减少伴随着更促动脉粥样硬化的高胆固醇血症发生，导致动脉粥样硬化发生不变。
Objective-Resident immune cells are a hallmark of atherosclerotic lesions. The sphingolipid analogue drug FTY720 mediates retrafficking of immune cells and inhibits their homing to inflammatory sites. We have evaluated the effect of FTY720 on atherogenesis and lipid metabolism.Methods and Results-ApoE(-/-) mice on a normal laboratory diet received oral FTY720 for 12 weeks, which led to a 2.4-fold increase in serum cholesterol ( largely VLDL fraction) and a 1.8-fold increase in hepatic HMGCoA reductase mRNA. FTY720 increased plasma sphingosine-1-phosphate and induced marked peripheral blood lymphopenia. A discoordinate modulation of B, T and monocyte cell numbers was found in peripheral lymphoid organs. Overall depletion of T cells was accompanied by a relative ( 2-fold) increase in regulatory T cell content paralleled by a similar increase in effector memory T cells ( CD4+CD44hiCD62lo) as absolute numbers of both subpopulations remained essentially unchanged. Lymphocyte function was unaltered as indicated by anti-OxLDL antibodies and T cell proliferation. There were no changes in atherosclerotic lesions in early and established atherosclerosis.Conclusions-FTY720 mediated peripheral lymphocyte depletion and retrafficking without altering function and overall balance of pro- and antiatherogenic lymphocyte populations. A net decrease in lymphocyte numbers occurred concomitantly with a more proatherogenic hypercholesterolemia resulting in unaltered atherogenesis.