Vascular accumulation of Lp(a): in vivo analysis of the role of lysine-binding sites using recombinant adenovirus.
Despite the importance of lipoprotein(a) [Lp(a)] as an atherogenic risk factor, very little information, especially from in vivo studies, is available concerning which structural features of apo(a) contribute to the interactions of Lp(a) with the vessel wall and its proatherogenic properties. Nearly all the proposed and proven activities of apolipoprotein(a) [apo(a)] focus on its high degree of sequence homology with plasminogen and the possibility that structural features shared by these two molecules contribute to the atherogenesis associated with high Lp(a) plasma levels in humans. In these studies, we examined the properties of three forms of Lp(a) differing at postulated lysine-binding domains contained in the constituent apo(a). We used the recombinant adenoviral gene delivery system to produce apo(a) in the plasma of human apoB transgenic mice, resulting in high levels of Lp(a) similar to those found in the plasma of humans. By comparison of in vitro lysine-binding properties of these forms of Lp(a) with measurements of Lp(a) vascular accumulation in the mice, we have demonstrated that lysine-binding defective forms of Lp(a) have a diminished capacity for vascular accumulation in vivo.
Hughes
S D
SD
Lawrence Berkeley National Laboratory, Life Sciences Division, Human Genome Center, Berkeley, CA 94720, USA.
Rubin
E M
EM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000737:chemistry; D001054:Apolipoproteins A / Q000737:chemistry* / Q000235:genetics; D001055:Apolipoproteins B / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology; D001665:Binding Sites / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood / Q000502:physiology; D008239:Lysine / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed / Q000235:genetics
D001054:Apolipoproteins A; D001055:Apolipoproteins B; D017270:Lipoprotein(a); D008239:Lysine