Inoue Shujiro, Egashira Kensuke, Ni Weihua, Kitamoto Shiro, Usui Makoto, Otani Kisho, Ishibashi Minako, Hiasa Ken-ichi, Nishida Ken-ichi, Takeshita Akira
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Circulation. 2002 Nov 19;106(21):2700-6. doi: 10.1161/01.cir.0000038140.80105.ad.
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.
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.
The results of the present study suggest that the inflammatory responses mediated by MCP-1 are important in atherosclerosis and its complications.
单核细胞浸润至动脉壁及其激活是动脉粥样硬化发生的核心事件。因此，单核细胞趋化蛋白-1（MCP-1）可能是抗动脉粥样硬化发生的新型治疗靶点。我们及其他研究者最近报道，阻断或消除MCP-1通路可减轻高胆固醇血症小鼠动脉粥样硬化斑块形成的起始过程。然而，MCP-1阻断是否能限制已形成病变的进展或使其不稳定仍不清楚。
我们在此报告，通过转染MCP-1基因的N端缺失突变体来阻断MCP-1，可限制高胆固醇血症小鼠主动脉根部已存在的动脉粥样硬化病变的进展。此外，阻断MCP-1可使病变组成转变为更稳定的表型，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蛋白。该策略降低了动脉粥样硬化斑块中CD40及CD40配体的表达，并使趋化因子（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-1β和转化生长因子β1）基因表达的增加恢复正常。这些数据表明，MCP-1是已形成的动脉粥样硬化斑块进展和不稳定的核心介质。
本研究结果提示，由MCP-1介导的炎症反应在动脉粥样硬化及其并发症中起重要作用。
