title: Subendothelial retention of atherogenic lipoproteins in early atherosclerosis.
abstract: Complications of atherosclerosis are the most common cause of death in Western societies. Among the many risk factors identified by epidemiological studies, only elevated levels of lipoproteins containing apolipoprotein (apo) B can drive the development of atherosclerosis in humans and experimental animals even in the absence of other risk factors. However, the mechanisms that lead to atherosclerosis are still poorly understood. We tested the hypothesis that the subendothelial retention of atherogenic apoB-containing lipoproteins is the initiating event in atherogenesis. The extracellular matrix of the subendothelium, particularly proteoglycans, is thought to play a major role in the retention of atherogenic lipoproteins. The interaction between atherogenic lipoproteins and proteoglycans involves an ionic interaction between basic amino acids in apoB100 and negatively charged sulphate groups on the proteoglycans. Here we present direct experimental evidence that the atherogenicity of apoB-containing low-density lipoproteins (LDL) is linked to their affinity for artery wall proteoglycans. Mice expressing proteoglycan-binding-defective LDL developed significantly less atherosclerosis than mice expressing wild-type control LDL. We conclude that subendothelial retention of apoB100-containing lipoprotein is an early step in atherogenesis.
authors.affiliation: Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Göteborg S-4345, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Skålén
authors.forename: Maria
authors.initials: M
authors.lastname: Gustafsson
authors.forename: Ellen Knutsen
authors.initials: EK
authors.lastname: Rydberg
authors.forename: Lillemor Mattsson
authors.initials: LM
authors.lastname: Hultén
authors.forename: Olov
authors.initials: O
authors.lastname: Wiklund
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Innerarity
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001011:Aorta; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000097:blood / Q000235:genetics / Q000378:metabolism; D001161:Arteriosclerosis / Q000097:blood* / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D001667:Binding, Competitive; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D004036:Diet, Atherogenic; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D006801:Humans; D008074:Lipoproteins / Q000097:blood* / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D011973:Receptors, LDL / Q000097:blood / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D011994:Recombinant Proteins; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol