title: Low density lipoprotein receptor-negative mice expressing human apolipoprotein B-100 develop complex atherosclerotic lesions on a chow diet: no accentuation by apolipoprotein(a).
abstract: We have generated mice with markedly elevated plasma levels of human low density lipoprotein (LDL) and reduced plasma levels of high density lipoprotein. These mice have no functional LDL receptors [LDLR-/-] and express a human apolipoprotein B-100 (apoB) transgene [Tg(apoB+/+)] with or without an apo(a) transgene [Tg(apoa+/-)]. Twenty animals (10 males and 10 females) of each of the following four genotypes were maintained on a chow diet: (i) LDLR-/-, (ii) LDLR-/-;Tg(apoa+/-), (iii) LDLR-/-;Tg(apoB+/+), and (iv)LDLR-/-;Tg(apoB+/+);Tg(apo+/-). The mice were killed at 6 mo, and the percent area of the aortic intimal surface that stained positive for neutral lipid was quantified. Mean percent areas of lipid staining were not significantly different between the LDLR-/- and LDLR-/-;Tg(apoa+/-) mice (1.0 +/- 0.2% vs. 1.4 +/- 0.3%). However, the LDLR-/-;Tg(apoB+/+) mice had approximately 15-fold greater mean lesion area than the LDLR-/- mice. No significant difference was found in percent lesion area in the LDLR-/-;Tg(apoB+/+) mice whether or not they expressed apo(a) [18.5 +/- 2.5%, without lipoprotein(a), Lp(a), vs. 16.0 +/- 1.7%, with Lp(a)]. Histochemical analyses of the sections from the proximal aorta of LDLR-/-;Tg(apoB+/+) mice revealed large, complex, lipid-laden atherosclerotic lesions that stained intensely with human apoB-100 antibodies. In mice expressing Lp(a), large amounts of apo(a) protein colocalized with apoB-100 in the lesions. We conclude that LDLR-/-; Tg(apoB+/+) mice exhibit accelerated atherosclerosis on a chow diet and thus provide an excellent animal model in which to study atherosclerosis. We found no evidence that apo(a) increased atherosclerosis in this animal model.
authors.affiliation: The Gladstone Institute of Cardiovascular Disease, University of California at San Francisco, San Francisco, CA 94110, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Sanan
authors.forename: D L
authors.initials: DL
authors.lastname: Newland
authors.forename: R
authors.initials: R
authors.lastname: Tao
authors.forename: S
authors.initials: S
authors.lastname: Marcovina
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: V
authors.initials: V
authors.lastname: Mooser
authors.forename: R E
authors.initials: RE
authors.lastname: Hammer
authors.forename: H H
authors.initials: HH
authors.lastname: Hobbs
mesh_terms: D000821:Animal Feed; D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D053299:Apolipoprotein B-100; D001053:Apolipoproteins / Q000096:biosynthesis* / Q000235:genetics; D001055:Apolipoproteins B / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D053241:Apoprotein(a); D001161:Arteriosclerosis / Q000097:blood / Q000235:genetics* / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D003433:Crosses, Genetic; D005260:Female; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D012727:Sex Characteristics
chemical_list: D053299:Apolipoprotein B-100; D001053:Apolipoproteins; D001055:Apolipoproteins B; D017270:Lipoprotein(a); D011973:Receptors, LDL; D002784:Cholesterol; D053241:Apoprotein(a)