P156	Macrophage low-density lipoprotein receptor-related protein deficiency enhances atherosclerosis.
1L.Hu, 1L.Boesten, 1M.Huisman, 1E.Meinders, 2L.Havekes, 3B.van Vlijmen, 1J.Tamsma
1Vascular Medicine, Department of General Internal Medicine, Leiden University Medical Center, Leiden, NL; 2TNO-Quality of Life, Gaubius Laboratory, Leiden, NL; 3Department of Hematology, Leiden University Medical Center, Leiden, NL.

Macrophages play an important role in the pathogenesis of atherosclerosis. Low-density lipoprotein (LDL) receptor-related protein (LRP) is a multiligand (>35 ligands) and multifunctional receptor involved in endocytotic clearance and signal transduction. Previous studies showed that hepatic and vascular smooth muscle cell LRP deficiency results in increased atherosclerosis and impaired vascular integrity. To date, the role of macrophage LRP in atherogenesis has not been elucidated. To study the role of macrophage LRP in atherogenesis we generated macrophage specific LRP deficient mice by crossbreeding lysozyme M Cre recombinase expressing mice with LRPflox/flox mice that were on a LDL receptor and apolipoprotein E double deficient background. Plasma cholesterol levels, lipoprotein profiles and blood monocyte counts were not affected by macrophage specific LRP deletion. At 18 weeks of age, total atherosclerotic lesion area in the aortic root was increased by 45% in macrophage LRP deficient mice as compared to control littermates (P=0.0008). LRP deficiency resulted in a lower relative number of early lesions and a higher relative number of advanced lesions (P=0.0186). Lesion macrophage content (corrected for lesion size) did not differ between LRP deficient animals and controls (P=0.664). However, lesion collagen content (corrected for lesion size) was 1.5–fold higher in macrophage LRP deficient mice as compared to controls (P=0.0052). Our data show that macrophage LRP deficiency results in more atherosclerotic lesions of that contain more collagen independent of plasma cholesterol. These findings demonstrate that LRP has an atheroprotective potential at the level of macrophages in addition to the previously shown characteristics of LRP in hepatocytes and smooth muscle cells.

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