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 l ow density lipoprotein (LDL) and reduced plasma levels of high density lipoprotein. These mice have no functional LDL receptors [LDLR-/-] an d 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 i ntimal 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 approximate to 15-fold greater mean lesion area than the LDLR-/- mice. No signifi cant difference was found in percent lesion area in the LDLR-/-;Tg(apo B(+/+)) mice whether or not they expressed apo(a) [18.5 +/- 2.5%, with out lipoprotein(a), Lp(a), vs. 16.0 +/- 1.7%, with Lp(a)]. Histochemic al analyses of the sections from the proximal aorta of LDLR-/-;Tg(apoB (+/+)) mice revealed large, complex, lipid-laden atherosclerotic lesio ns that stained intensely with human apoB-100 antibodies. in mice expr essing Lp(a), large amounts of apo(a) protein colocalized with apoB-10 0 in the lesions. We conclude that LDLR-/-;Tg(apoB(+/+)) mice exhibit accelerated atherosclerosis on a chow diet and thus provide an excelle nt animal model in which to study atherosclerosis. We found no evidenc e that apo(a) increased atherosclerosis in this animal model.