Low density lipoprotein receptor-negative mice expressing human apolipoprotein B-100 develop complex atherosclerotic lesions on a chow diet: no accentuation by apolipoprotein(a).
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.
Sanan
D A
DA
The Gladstone Institute of Cardiovascular Disease, University of California at San Francisco, San Francisco, CA 94110, USA.
Newland
D L
DL
Tao
R
R
Marcovina
S
S
Wang
J
J
Mooser
V
V
Hammer
R E
RE
Hobbs
H H
HH
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
D053299:Apolipoprotein B-100; D001053:Apolipoproteins; D001055:Apolipoproteins B; D017270:Lipoprotein(a); D011973:Receptors, LDL; D002784:Cholesterol; D053241:Apoprotein(a)