Differential influence of chemokine receptors CCR2 and CXCR3 in development of atherosclerosis in vivo.
| Autor: | Veillard NR; Division of Cardiology, Foundation for Medical Research, University Hospital Geneva, Geneva, Switzerland., Steffens S, Pelli G, Lu B, Kwak BR, Gerard C, Charo IF, Mach F |
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| Jazyk: | angličtina |
| Zdroj: | Circulation [Circulation] 2005 Aug 09; Vol. 112 (6), pp. 870-8. Date of Electronic Publication: 2005 Aug 01. |
| DOI: | 10.1161/CIRCULATIONAHA.104.520718 |
| Abstrakt: | Background: Recruitment of mononuclear leukocytes within atherosclerotic lesions is a critical step in atherogenesis. Mice lacking the chemokine receptor CCR2, highly expressed on macrophages but also on T lymphocytes, show a striking reduction of atherosclerotic lesion formation. The chemokine receptor CXCR3 is a marker of activated T helper type 1 lymphocytes, the principal T lymphocyte type detected within atheroma. We investigated whether the deletion of both of these 2 important receptors expressed on the principal inflammatory cells present in atheroma would further affect atherogenesis in vivo. Methods and Results: We crossed ApoE(-/-) mice with either CCR2(-/-) or CXCR3- mice and crossed ApoE(-/-) CCR2(-/-) mice with the ApoE(-/-) CXCR3- mice to generate a triple knockout strain. Analysis of atherosclerosis development after 10 weeks of high-cholesterol diet revealed differential effects on early atherosclerotic lesions in the abdominal aorta and on advanced lesions in aortic roots. ApoE(-/-) CXCR3- mice, but not the triple knockout mice, displayed significantly reduced atherosclerotic lesion development within abdominal aortas compared with ApoE(-/-) CCR2(-/-) and ApoE(-/-) mice. This reduction of lesion formation correlated with an upregulation of antiinflammatory molecules such as interleukin-10, interleukin-18BP, and endothelial nitric oxide synthase and with an increased number of regulatory T lymphocytes within atherosclerotic lesions. In contrast, lesion size development within the aortic roots was more enhanced in ApoE(-/-) and ApoE(-/-) CXCR3- mice compared with ApoE(-/-) CCR2(-/-) and triple knockout mice. Conclusions: Blocking chemokine signaling in vivo through deletion of the chemokine receptors CCR2 and CXCR3 has differential effects during atherogenesis. In addition, our results point to an important role of regulatory T lymphocytes during early atherogenesis. |
| Databáze: | MEDLINE |
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