Systemic MCP1/CCR2 blockade and leukocyte specific MCP1/CCR2 inhibition affect aortic aneurysm formation differently

Vivian de Waard, Ilze Bot, Saskia C.A. de Jager, Sara Talib, Kensuke Egashira, Margreet R. de Vries, Paul H.A. Quax, Erik A.L. Biessen, Theo J.C. van Berkel

研究成果: ジャーナルへの寄稿記事

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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.

元の言語英語
ページ(範囲)84-89
ページ数6
ジャーナルAtherosclerosis
211
発行部数1
DOI
出版物ステータス出版済み - 7 1 2010

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All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

これを引用

de Waard, V., Bot, I., de Jager, S. C. A., Talib, S., Egashira, K., de Vries, M. R., ... van Berkel, T. J. C. (2010). Systemic MCP1/CCR2 blockade and leukocyte specific MCP1/CCR2 inhibition affect aortic aneurysm formation differently. Atherosclerosis, 211(1), 84-89. https://doi.org/10.1016/j.atherosclerosis.2010.01.042