Specific abrogation of transforming growth factor-β signaling in T cells alters atherosclerotic lesion size and composition in mice
Specific abrogation of transforming growth factor-β signaling in T cells alters atherosclerotic lesion size and composition in mice
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DOI：
10.1182/blood-2003-05-1729
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发表时间：
2003-12-01
期刊：
影响因子：
20.3
通讯作者：
Groux, H
中科院分区：
文献类型：
--
作者：
Gojova, A;Brun, V;Groux, H
大量证据支持促炎介质在动脉粥样硬化性疾病进展和不稳定性中的作用。然而，只有很少的内源性机制被认为可以改变疾病的进展。其中一种机制被认为是由转化生长因子-β(转化生长因子-β)介导的。产生了在T细胞特异性启动子下表达显性阴性的转化生长因子-β受体II型的转基因小鼠。将转基因小鼠的骨髓移植到辐射低密度脂蛋白受体基因敲除小鼠(LDLR KO)中，随后喂养致动脉粥样硬化的饮食，导致受体小鼠中T细胞特异性阻断转化生长因子-β信号，并增加T细胞向辅助性T细胞1(Th1)和Th2表型的分化。与接受野生型骨髓移植的小鼠相比，这些小鼠的主动脉窦动脉粥样硬化病变大小显著减少。接受转基因骨髓移植的小鼠的动脉粥样硬化斑块显示T细胞渗透增加，主要组织相容性复合体(MHC)II类的表达增加，同时平滑肌细胞和胶原含量减少，这是一种可能容易破裂的斑块表型。这些结果首次证实了特异性和选择性T细胞-转化生长因子-β信号在动脉粥样硬化中的重要作用。(C)2003年，由美国血液病学会提供。
A large body of evidence supports a role for proinflammatory mediators in atherosclerotic disease progression and instability. However, only few endogenous mechanisms have been suggested that could alter disease progression. One such mechanism is thought to be mediated by transforming growth factor beta (TGF-beta). Transgenic mice that express a dominant-negative TGF-beta receptor type II under a T-cell-specific promoter were generated. Bone marrow transplantation from transgenic mice into irradiated low density lipoprotein receptor knock-out (LDLr KO) mice, subsequently fed an atherogenic diet, resulted in T-cell-specific blockade of TGF-beta signaling in the recipient mice and increased differentiation of T cells toward both T helper 1 (Th1) and Th2 phenotypes. These mice showed a significant decrease in atherosclerotic lesion size in the aortic sinus compared with mice receiving transplants with the wildtype bone marrow. Atherosclerotic plaques of mice receiving transplants with the transgenic bone marrow showed increased T-cell infiltration and expression of major histocompatability complex (MHC) class II, along with a decrease in smooth muscle cell and collagen content, a plaque phenotype that is potentially vulnerable to rupture. These results identify for the first time an important role for specific and selective T-cell-TGF-beta signaling in atherosclerosis. (C) 2003 by The American Society of Hematology.