Anti-monocyte chemoattractant protein-1 gene therapy limits progression and destabilization of established atherosclerosis in apolipoprotein E-knockout mice
Anti-monocyte chemoattractant protein-1 gene therapy limits progression and destabilization of established atherosclerosis in apolipoprotein E-knockout mice
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DOI：
10.1161/01.cir.0000038140.80105.ad
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发表时间：
2002-11-19
期刊：
影响因子：
37.8
通讯作者：
Takeshita, A
中科院分区：
文献类型：
--
作者：
Inoue, S;Egashira, K;Takeshita, A
背景-单核细胞浸润到动脉壁及其激活是动脉粥样硬化形成的中心事件。因此，单核细胞趋化蛋白-1（MCP-1）可能成为抗动脉粥样硬化的新靶点。我们和其他人最近报道，阻断或废除MCP-1通路可减弱高胆固醇血症小鼠动脉粥样硬化形成的起始。目前还不清楚，但是，是否封锁MCP-1可以限制进展或不稳定的建立insulines.Methods和Results-We在这里报告，封锁MCP-1的MCP-1基因的N-末端缺失突变体，限制了预先存在的动脉粥样硬化病变的进展，在主动脉根部的高胆固醇血症小鼠。此外，MCP-1的阻断将病变组成改变为更稳定的表型，即含有更少的巨噬细胞和淋巴细胞、更少的脂质以及更多的平滑肌细胞和胶原。该策略降低了动脉粥样硬化斑块中CD 40和CD 40配体的表达，并使增加的趋化因子（RANTES和MCP-1）和细胞因子（肿瘤坏死因子α、白细胞介素-6、白细胞介素-1 β和转化生长因子β（1））基因表达正常化。这些数据表明，MCP-1是一个中央调解人的进展和不稳定的建立atherosoma. Conclusions-本研究的结果表明，MCP-1介导的炎症反应是重要的动脉粥样硬化及其并发症。
Background-Monocyte infiltration into the arterial wall and its activation is the central event in atherogenesis. Thus, monocyte chemoattractant protein-1 (MCP-1) might be a novel therapeutic target against atherogenesis. We and others recently reported that blockade or abrogation of the MCP-1 pathway attenuates the initiation of atheroma formation in hypercholesterolemic mice. It remains unclear, however, whether blockade of MCP-1 can limit progression or destabilization of established lesions.Methods and Results-We report here that blockade of MCP-1 by transfecting an N-terminal deletion mutant of the MCP-1 gene limited progression of preexisting atherosclerotic lesions in the aortic root in hypercholesterolemic mice. In addition, blockade of MCP-1 changed the lesion composition into a more stable phenotype, ie, containing fewer macrophages and lymphocytes, less lipid, and more smooth muscle cells and collagen. This strategy decreased expression of CD40 and the CD40 ligand in the atherosclerotic plaque and normalized the increased chemokine (RANTES and MCP-1) and cytokine (tumor necrosis factor alpha, interleukin-6, interleukin-1beta, and transforming growth factor beta(1)) gene expression. These data suggest that MCP-1 is a central mediator in the progression and destabilization of established atheroma.Conclusions-The results of the present study suggest that the inflammatory responses mediated by MCP-1 are important in atherosclerosis and its complications.