Characterization of atherosclerosis in LDL receptor knockout mice: macrophage accumulation correlates with rapid and sustained expression of aortic MCP-1/JE

Atherosclerosis and the expression of monocyte chemoattractant protein-1 (M CP-I) were quantified in low density lipoprotein receptor knockout (LDLR KO ) mice fed 1.25% cholesterol (study # 1) or 0.2% cholesterol (study # 2). I n study # 1 plasma total cholesterols leveled-off at 1800 mg/dl whereas pla sma triglycerides remained low. In en face specimens of the aortic root and arch, intimal foam cells plus extracellular lipid particles accumulated an d by 8 weeks the fatty streak surface area had rapidly expanded at both sit es. In study # 2, total cholesterols averaged 400 mg/dl and fatty streaks w ere 2-3-fold smaller compared to those in study # 1. In study # 3, LDLR KO mice were fed chow or 1.25% cholesterol, and immunostaining demonstrated a few Mac-2-positive intimal macrophages in mice fed chow, and during the fir st 10 weeks of hypercholesterolemia the number of intimal macrophages incre ased continuously. In chow-fed mice (0 weeks) there was little MCP-1 in the aorta. After 2 days of hypercholesterolemia intimal macrophages stained fo r MCP-1, and during the next 10 weeks recently recruited arterial macrophag es also expressed MCP-1. Macrophage accumulation was highly correlated with MCP-I expression. In study # 4, feeding LDLR KO mice 1.25% cholesterol for 6 months produced atherosclerotic plaques at both sites and they contained a fibrous cap of smooth muscle cells, macrophage-foam cells, connective ti ssue and cholesterol crystals. In summary, LDLR KO mice fed cholesterol dev elop fatty streaks that transform into fibrous plaques. Hypercholesterolemi a rapidly triggers MCP-I expression in resident intimal macrophages, which is followed by the accumulation of more macrophages that also express MCP-1 , suggesting that this chemokine may both initiate and amplify monocyte rec ruitment to the artery wall during early atherogenesis. (C) 2000 Elsevier S cience Ireland Ltd. All rights reserved.