Low density lipoprotein receptor-negative expressing human apolipoprotein B-100 develop complex atherosclerotic lesions on a chow diet

No accentuation by apolipoprotein(a)

D. A. Sanan, D. L. Newland, R. Tao, S. Marcovina, J. Wang, V. Mooser, Robert E Hammer, Helen H Hobbs

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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 animus (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 ≃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.

Original languageEnglish (US)
Pages (from-to)4544-4549
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number8
DOIs
StatePublished - Apr 14 1998

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Apolipoprotein B-100
Apoprotein(a)
LDL Receptors
Diet
Apolipoproteins A
Atherosclerosis
Transgenes
Lipids
Animal Models
Tunica Intima
Lipoprotein(a)
HDL Lipoproteins
LDL Lipoproteins
Aorta

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

@article{66741d0ba91f46fcb3a58c9e1024a323,
title = "Low density lipoprotein receptor-negative 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 animus (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 ≃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.",
author = "Sanan, {D. A.} and Newland, {D. L.} and R. Tao and S. Marcovina and J. Wang and V. Mooser and Hammer, {Robert E} and Hobbs, {Helen H}",
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language = "English (US)",
volume = "95",
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TY - JOUR

T1 - Low density lipoprotein receptor-negative expressing human apolipoprotein B-100 develop complex atherosclerotic lesions on a chow diet

T2 - No accentuation by apolipoprotein(a)

AU - Sanan, D. A.

AU - Newland, D. L.

AU - Tao, R.

AU - Marcovina, S.

AU - Wang, J.

AU - Mooser, V.

AU - Hammer, Robert E

AU - Hobbs, Helen H

PY - 1998/4/14

Y1 - 1998/4/14

N2 - 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 animus (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 ≃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.

AB - 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 animus (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 ≃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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JF - Proceedings of the National Academy of Sciences of the United States of America

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