title: Modification of apolipoprotein(a) lysine binding site reduces atherosclerosis in transgenic mice.
abstract: Lipoprotein(a) contributes to the development of atherosclerosis through the binding of its plasminogen-like apolipoprotein(a) component to fibrin and other plasminogen substrates. Apolipoprotein(a) contains a major lysine binding site in one of its kringle domains. Destruction of this site by mutagenesis greatly reduces the binding of apolipoprotein(a) to lysine and fibrin. Transgenic mice expressing this mutant form of apolipoprotein(a) as well as mice expressing wild-type apolipoprotein(a) have been created in an inbred mouse strain. The wild-type apolipoprotein(a) transgenic mice have a fivefold increase in the development of lipid lesions, as well as a large increase in the focal deposition of apolipoprotein(a) in the aorta, compared with the lysine binding site mutant strain and to nontransgenic littermates. The results demonstrate the key role of this lysine binding site in the pathogenic activity of apolipoprotein(a) in a murine model system.
authors.affiliation: Falk Cardiovascular Research Center, Stanford University School of Medicine, Stanford, California 94305-5246, USA.
authors.forename: N W
authors.initials: NW
authors.lastname: Boonmark
authors.forename: X J
authors.initials: XJ
authors.lastname: Lou
authors.forename: Z J
authors.initials: ZJ
authors.lastname: Yang
authors.forename: K
authors.initials: K
authors.lastname: Schwartz
authors.forename: J L
authors.initials: JL
authors.lastname: Zhang
authors.forename: E M
authors.initials: EM
authors.lastname: Rubin
authors.forename: R M
authors.initials: RM
authors.lastname: Lawn
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000503:physiopathology; D001161:Arteriosclerosis / Q000378:metabolism* / Q000503:physiopathology; D001665:Binding Sites / Q000235:genetics; D005337:Fibrin / Q000378:metabolism; D017270:Lipoprotein(a) / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed
chemical_list: D017270:Lipoprotein(a); D005337:Fibrin; D008239:Lysine