Abstract 15367: Dynamics of Macrophage Infiltration into the Arterial Wall at Different Stages of Atherosclerotic Lesion Development and Dependency on Macrophage ABCA1 Expression
Atherosclerosis is a progressive disease characterized by the accumulation of lipid-laden macrophages in the arterial wall. Previously, we have shown that macrophage ABCA1 deficiency accelerates atherosclerosis, while macrophage ABCA1 overexpression inhibits progression of the disease. The anti-atherogenic effects of ABCA1 are primarily attributed to its role in cellular cholesterol efflux. However, several lines of evidence also indicate a role for macrophage ABCA1 in inflammation and macrophage recruitment into tissues. In this study the importance of ABCA1 for the recruitment of monocytes into atherosclerotic lesions was studied. Hereto, LDL receptor knockout mice with atherosclerotic lesions of increasing severity were transplanted with bone marrow lacking or overexpression ABCA1 which also expressed enhanced green fluorescent protein (EGFP) to track donor-derived cells during further lesion progression. Continuous recruitment of donor-derived macrophages into pre-existing initial lesions led to further growth of the lesions. Interestingly, deletion of macrophage ABCA1 resulted in a mild increase in macrophage influx into these initial lesions (mean EGFP+ F4/80+ area: 468±107x103 μm2, n=12, p=0.06 as compared to 389±44x103 μm2, n=12 for control macrophages), while influx of ABCA1-overexpressing macrophages was significantly lower (291±28x103 μm2, n=8, p<0.01). The recruitment of monocytes to more advanced lesions was largely impaired, most likely due to fibrous cap formation. As a result, no effect of ABCA1 deletion or overexpression in macrophages was observed on infiltration into advanced lesions. In conclusion, the dynamics of macrophage infiltration into atherosclerotic lesions depends on the severity of the lesion. Furthermore, ABCA1 not only protects against lesion development by promoting macrophage cholesterol efflux, but also by limiting the influx of monocytes into the arterial wall.
- © 2010 by American Heart Association, Inc.