Low density lipoprotein receptor-negative mice expressing human apolipoprotein B-100 develop complex atherosclerotic lesions on a chow diet: No accentuation by apolipoprotein(a)

May 16, 1998Proceedings of the National Academy of Sciences of the United States of America

Mice lacking LDL receptors with human apolipoprotein B-100 develop complex artery plaques on a normal diet, unaffected by apolipoprotein(a)

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Abstract

Mice with human apolipoprotein B-100 exhibited approximately 15-fold greater mean lesion area compared to LDL receptor-deficient mice.

Mice lacking functional LDL receptors and expressing human apolipoprotein B-100 developed significantly larger atherosclerotic lesions.
Mean percent area of lipid staining was similar between LDLR-/- and LDLR-/-;Tg(apoa+/-) mice.
No significant difference in lesion area was observed in LDLR-/-;Tg(apoB+/+) mice regardless of the presence of apo(a).
Histological analysis showed complex, lipid-rich lesions in LDLR-/-;Tg(apoB+/+) mice that stained positively for human apoB-100.
Apo(a) protein was found to colocalize with apoB-100 in lesions of mice expressing lipoprotein(a), but did not appear to exacerbate atherosclerosis.

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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.

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Low density lipoprotein receptor-negative mice expressing human apolipoprotein B-100 develop complex atherosclerotic lesions on a chow diet: No accentuation by apolipoprotein(a)

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