title: Characterization of atherosclerosis in LDL receptor knockout mice: macrophage accumulation correlates with rapid and sustained expression of aortic MCP-1/JE.
abstract: Atherosclerosis and the expression of monocyte chemoattractant protein-1 (MCP-1) were quantified in low density lipoprotein receptor knockout (LDLR KO) mice fed 1.25% cholesterol (study #1) or 0.2% cholesterol (study #2). In study #1 plasma total cholesterols leveled-off at 1800 mg/dl whereas plasma triglycerides remained low. In en face specimens of the aortic root and arch, intimal foam cells plus extracellular lipid particles accumulated and by 8 weeks the fatty streak surface area had rapidly expanded at both sites. In study #2, total cholesterols averaged 400 mg/dl and fatty streaks were 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 first 10 weeks of hypercholesterolemia the number of intimal macrophages increased continuously. In chow-fed mice (0 weeks) there was little MCP-1 in the aorta. After 2 days of hypercholesterolemia intimal macrophages stained for MCP-1, and during the next 10 weeks recently recruited arterial macrophages also expressed MCP-1. Macrophage accumulation was highly correlated with MCP-1 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 tissue and cholesterol crystals. In summary, LDLR KO mice fed cholesterol develop fatty streaks that transform into fibrous plaques. Hypercholesterolemia rapidly triggers MCP-1 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 recruitment to the artery wall during early atherogenesis.
authors.affiliation: Department of Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton NJ 08543-4000, USA. mark.kowala@bms.com
authors.forename: M C
authors.initials: MC
authors.lastname: Kowala
authors.forename: R
authors.initials: R
authors.lastname: Recce
authors.forename: S
authors.initials: S
authors.lastname: Beyer
authors.forename: C
authors.initials: C
authors.lastname: Gu
authors.forename: M
authors.initials: M
authors.lastname: Valentine
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology*; D018932:Chemokine CCL2 / Q000032:analysis*; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D008074:Lipoproteins / Q000097:blood; D008264:Macrophages / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D011336:Probability; D011973:Receptors, LDL / Q000378:metabolism; D012016:Reference Values; D012680:Sensitivity and Specificity; D012984:Software; D018709:Statistics, Nonparametric; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology
chemical_list: D018932:Chemokine CCL2; D002791:Cholesterol, Dietary; D008074:Lipoproteins; D011973:Receptors, LDL