Macrophage-specific expression of human apolipoprotein E reduces atherosclerosis in hypercholesterolemic apolipoprotein E-null mice

S. Bellosta, R. W. Mahley, D. A. Sanan, J. Murata, D. L. Newland, J. M. Taylor, R. E. Pitas

Research output: Contribution to journalArticle

Abstract

apoE deficiency causes hyperlipidemia and premature atherosclerosis. To determine if macrophage-specific expression of apoE would decrease the extent of atherosclerosis, we expressed human apoE in macrophages of apoE-null mice (apoE(-/-)) and assessed the effect on lipid accumulation in cells of the arterial wall. Macrophage-specific expression of human apoE in normal mice was obtained by use of the visna virus LTR. These animals were bred with apoE(-/-) mice to produce animals hemizygous for expression of human apoE in macrophages in the absence of murine apoE (apoE(-/-),hTgE(+/10)). Low levels of human apoE mRNA were present in liver and spleen and high levels in lung and peritoneal macrophages. Human apoE was secreted by peritoneal macrophages and was detected in Kupffer cells of the liver. Human apoE in the plasma of apoE(-/-),hTgE(+/10) mice (n = 30) was inversely correlated (P <0.005) with the plasma cholesterol concentration. After 15 wk on a normal chow diet, atherosclerosis was assessed in apoE(-/-),hTgE(+/10) animals and in apoE(-/- ),hTgE(0/10) littermates matched for plasma cholesterol level (~450 mg/dl) and lipoprotein profile. There was significantly less atherosclerosis in both the aortic sinus and in the proximal aorta (P <0.0001) in the animals expressing the human apoE transgene. In apo-E(-/-),hTgE(+/10) animals, which had detectable atherosclerotic lesions, human apoE was detected in the secretory apparatus of macrophage-derived foam cells in the arterial wall. The data demonstrate that expression of apoE by macrophages is antiatherogenic even in the presence of high levels of atherogenic lipoproteins. The data suggest that apoE prevents atherosclerosis by promoting cholesterol efflux from cells of the arterial wall.

Original languageEnglish
Pages (from-to)2170-2179
Number of pages10
JournalJournal of Clinical Investigation
Volume96
Issue number5
Publication statusPublished - 1995

Fingerprint

Apolipoproteins E
Atherosclerosis
Macrophages
Cholesterol
Peritoneal Macrophages
Cell Wall
Lipoproteins
Visna-maedi virus
Sinus of Valsalva
Foam Cells
Kupffer Cells
Liver

Keywords

  • apoE deficiency
  • atherogenesis
  • hyperlipidemia
  • lipoproteins
  • transgenic mice

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bellosta, S., Mahley, R. W., Sanan, D. A., Murata, J., Newland, D. L., Taylor, J. M., & Pitas, R. E. (1995). Macrophage-specific expression of human apolipoprotein E reduces atherosclerosis in hypercholesterolemic apolipoprotein E-null mice. Journal of Clinical Investigation, 96(5), 2170-2179.

Macrophage-specific expression of human apolipoprotein E reduces atherosclerosis in hypercholesterolemic apolipoprotein E-null mice. / Bellosta, S.; Mahley, R. W.; Sanan, D. A.; Murata, J.; Newland, D. L.; Taylor, J. M.; Pitas, R. E.

In: Journal of Clinical Investigation, Vol. 96, No. 5, 1995, p. 2170-2179.

Research output: Contribution to journalArticle

Bellosta, S, Mahley, RW, Sanan, DA, Murata, J, Newland, DL, Taylor, JM & Pitas, RE 1995, 'Macrophage-specific expression of human apolipoprotein E reduces atherosclerosis in hypercholesterolemic apolipoprotein E-null mice', Journal of Clinical Investigation, vol. 96, no. 5, pp. 2170-2179.
Bellosta, S. ; Mahley, R. W. ; Sanan, D. A. ; Murata, J. ; Newland, D. L. ; Taylor, J. M. ; Pitas, R. E. / Macrophage-specific expression of human apolipoprotein E reduces atherosclerosis in hypercholesterolemic apolipoprotein E-null mice. In: Journal of Clinical Investigation. 1995 ; Vol. 96, No. 5. pp. 2170-2179.
@article{58827c05a6c74ab8bdfce88a7ea4cfb9,
title = "Macrophage-specific expression of human apolipoprotein E reduces atherosclerosis in hypercholesterolemic apolipoprotein E-null mice",
abstract = "apoE deficiency causes hyperlipidemia and premature atherosclerosis. To determine if macrophage-specific expression of apoE would decrease the extent of atherosclerosis, we expressed human apoE in macrophages of apoE-null mice (apoE(-/-)) and assessed the effect on lipid accumulation in cells of the arterial wall. Macrophage-specific expression of human apoE in normal mice was obtained by use of the visna virus LTR. These animals were bred with apoE(-/-) mice to produce animals hemizygous for expression of human apoE in macrophages in the absence of murine apoE (apoE(-/-),hTgE(+/10)). Low levels of human apoE mRNA were present in liver and spleen and high levels in lung and peritoneal macrophages. Human apoE was secreted by peritoneal macrophages and was detected in Kupffer cells of the liver. Human apoE in the plasma of apoE(-/-),hTgE(+/10) mice (n = 30) was inversely correlated (P <0.005) with the plasma cholesterol concentration. After 15 wk on a normal chow diet, atherosclerosis was assessed in apoE(-/-),hTgE(+/10) animals and in apoE(-/- ),hTgE(0/10) littermates matched for plasma cholesterol level (~450 mg/dl) and lipoprotein profile. There was significantly less atherosclerosis in both the aortic sinus and in the proximal aorta (P <0.0001) in the animals expressing the human apoE transgene. In apo-E(-/-),hTgE(+/10) animals, which had detectable atherosclerotic lesions, human apoE was detected in the secretory apparatus of macrophage-derived foam cells in the arterial wall. The data demonstrate that expression of apoE by macrophages is antiatherogenic even in the presence of high levels of atherogenic lipoproteins. The data suggest that apoE prevents atherosclerosis by promoting cholesterol efflux from cells of the arterial wall.",
keywords = "apoE deficiency, atherogenesis, hyperlipidemia, lipoproteins, transgenic mice",
author = "S. Bellosta and Mahley, {R. W.} and Sanan, {D. A.} and J. Murata and Newland, {D. L.} and Taylor, {J. M.} and Pitas, {R. E.}",
year = "1995",
language = "English",
volume = "96",
pages = "2170--2179",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "5",

}

TY - JOUR

T1 - Macrophage-specific expression of human apolipoprotein E reduces atherosclerosis in hypercholesterolemic apolipoprotein E-null mice

AU - Bellosta, S.

AU - Mahley, R. W.

AU - Sanan, D. A.

AU - Murata, J.

AU - Newland, D. L.

AU - Taylor, J. M.

AU - Pitas, R. E.

PY - 1995

Y1 - 1995

N2 - apoE deficiency causes hyperlipidemia and premature atherosclerosis. To determine if macrophage-specific expression of apoE would decrease the extent of atherosclerosis, we expressed human apoE in macrophages of apoE-null mice (apoE(-/-)) and assessed the effect on lipid accumulation in cells of the arterial wall. Macrophage-specific expression of human apoE in normal mice was obtained by use of the visna virus LTR. These animals were bred with apoE(-/-) mice to produce animals hemizygous for expression of human apoE in macrophages in the absence of murine apoE (apoE(-/-),hTgE(+/10)). Low levels of human apoE mRNA were present in liver and spleen and high levels in lung and peritoneal macrophages. Human apoE was secreted by peritoneal macrophages and was detected in Kupffer cells of the liver. Human apoE in the plasma of apoE(-/-),hTgE(+/10) mice (n = 30) was inversely correlated (P <0.005) with the plasma cholesterol concentration. After 15 wk on a normal chow diet, atherosclerosis was assessed in apoE(-/-),hTgE(+/10) animals and in apoE(-/- ),hTgE(0/10) littermates matched for plasma cholesterol level (~450 mg/dl) and lipoprotein profile. There was significantly less atherosclerosis in both the aortic sinus and in the proximal aorta (P <0.0001) in the animals expressing the human apoE transgene. In apo-E(-/-),hTgE(+/10) animals, which had detectable atherosclerotic lesions, human apoE was detected in the secretory apparatus of macrophage-derived foam cells in the arterial wall. The data demonstrate that expression of apoE by macrophages is antiatherogenic even in the presence of high levels of atherogenic lipoproteins. The data suggest that apoE prevents atherosclerosis by promoting cholesterol efflux from cells of the arterial wall.

AB - apoE deficiency causes hyperlipidemia and premature atherosclerosis. To determine if macrophage-specific expression of apoE would decrease the extent of atherosclerosis, we expressed human apoE in macrophages of apoE-null mice (apoE(-/-)) and assessed the effect on lipid accumulation in cells of the arterial wall. Macrophage-specific expression of human apoE in normal mice was obtained by use of the visna virus LTR. These animals were bred with apoE(-/-) mice to produce animals hemizygous for expression of human apoE in macrophages in the absence of murine apoE (apoE(-/-),hTgE(+/10)). Low levels of human apoE mRNA were present in liver and spleen and high levels in lung and peritoneal macrophages. Human apoE was secreted by peritoneal macrophages and was detected in Kupffer cells of the liver. Human apoE in the plasma of apoE(-/-),hTgE(+/10) mice (n = 30) was inversely correlated (P <0.005) with the plasma cholesterol concentration. After 15 wk on a normal chow diet, atherosclerosis was assessed in apoE(-/-),hTgE(+/10) animals and in apoE(-/- ),hTgE(0/10) littermates matched for plasma cholesterol level (~450 mg/dl) and lipoprotein profile. There was significantly less atherosclerosis in both the aortic sinus and in the proximal aorta (P <0.0001) in the animals expressing the human apoE transgene. In apo-E(-/-),hTgE(+/10) animals, which had detectable atherosclerotic lesions, human apoE was detected in the secretory apparatus of macrophage-derived foam cells in the arterial wall. The data demonstrate that expression of apoE by macrophages is antiatherogenic even in the presence of high levels of atherogenic lipoproteins. The data suggest that apoE prevents atherosclerosis by promoting cholesterol efflux from cells of the arterial wall.

KW - apoE deficiency

KW - atherogenesis

KW - hyperlipidemia

KW - lipoproteins

KW - transgenic mice

UR - http://www.scopus.com/inward/record.url?scp=0028883354&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028883354&partnerID=8YFLogxK

M3 - Article

C2 - 7593602

AN - SCOPUS:0028883354

VL - 96

SP - 2170

EP - 2179

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 5

ER -