Systemic MCP1/CCR2 blockade and leukocyte specific MCP1/CCR2 inhibition affect aortic aneurysm formation differently
Systemic MCP1/CCR2 blockade and leukocyte specific MCP1/CCR2 inhibition affect aortic aneurysm formation differently
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DOI：
10.1016/j.atherosclerosis.2010.01.042
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发表时间：
2010-07-01
期刊：
影响因子：
5.3
通讯作者：
van Berkel, Theo J. C.
中科院分区：
文献类型：
--
作者：
de Waard, Vivian;Bot, Ilze;van Berkel, Theo J. C.
目的：CCR2 是单核细胞趋化蛋白 1 (MCP1) 的受体，参与动脉粥样硬化和腹主动脉瘤 (AAA)。在这里，我们探索了对 MCP1/CCR2 通路的潜在有益阻断。方法：我们在先前存在动脉粥样硬化病变的老年载脂蛋白 E 缺陷小鼠中应用了 AAA 模型。这些小鼠接受了两种治疗策略。首先，MCP1 的显性失活形式在股骨肌肉中过度表达，导致 MCP1-7ND (7ND) 的循环水平与天然 MCP1 竞争。在第二种方法中，使用感染了含有 CCR2 siRNA 的慢病毒构建体的骨髓细胞进行骨髓移植，以特异性抑制白细胞 CCR2 表达。 结果：两种策略均不影响晚期动脉粥样硬化斑块的病变大小。然而，7ND 诱导了更多纤维斑块表型。然而，令人惊讶的是，在 7ND 组中观察到 AAA 的数量和严重程度有增加的趋势。在 7ND 组中，动脉瘤中的平滑肌细胞显示出磷酸化信号转导器和转录激活子 5 的减少（STAT5，P < 0.01），这表明增殖和迁移（伤口愈合）反应减少。这大概导致了 AAA 发展的增加。相反，siRNA 诱导的白细胞 CCR2 抑制导致动脉瘤形成显着抑制。总之，MCP1/CCR2 通路的全身抑制会导致晚期动脉粥样硬化病变中出现纤维斑块表型，但对 AAA 形成具有潜在的不利影响，这意味着对于有益的整体治疗方法，针对白细胞 CCR2 的特异性抑制是至关重要的。 (C) 2010 Elsevier Ireland Ltd. 保留所有权利。
Objective: CCR2, the receptor for monocyte chemoattractant protein 1 (MCP1), is involved in atherosclerosis and abdominal aortic aneurysms (AAAs). Here, we explored the potential beneficial blockade of the MCP1/CCR2 pathway.Methods: We applied an AAA model in aging apolipoprotein E deficient mice with pre-existing atherosclerotic lesions. These mice were subjected to two therapeutic strategies. First, a dominant negative form of MCP1 was overexpressed in femoral muscles, resulting in circulating levels of MCP1-7ND (7ND), competing with native MCP1. In the second approach, bone marrow transplantation was performed using bone marrow cells that were infected with a lentiviral construct containing siRNA for CCR2, to specifically inhibit only leukocyte CCR2 expression.Results: Both strategies did not influence lesion size of the advanced atherosclerotic plaques. However, 7ND induced a more fibrous plaque phenotype. Yet, surprisingly a trend in increased number and severity of AAA was observed in the 7ND group. Smooth muscle cells in the aneurysm showed decreased phosphorylated signal transducer and activator of transcription five (STAT5, P < 0.01) in the 7ND group, which is indicative for a decreased proliferative and migratory (wound healing) response. This presumably resulted in the increased AAA development. In contrast, siRNA-induced inhibition of CCR2 in leukocytes led to a significant inhibition in aneurysm formation. In conclusion, systemic inhibition of the MCP1/CCR2 pathway leads to a fibrous plaque phenotype in the advanced atherosclerotic lesions, but to potential adverse effects on AAA formation, implying that for a beneficial overall therapeutic approach, specific inhibitory targeting of leukocyte CCR2 will be essential. (C) 2010 Elsevier Ireland Ltd. All rights reserved.