Macrophage apolipoprotein E reduces atherosclerosis and prevents premature death in apolipoprotein E and scavenger receptor-class BI double-knockout mice

Hong Yu, Wenwu Zhang, Patricia G. Yancey, Mark J. Koury, Youmin Zhang, Sergio Fazio, MacRae F. Linton

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Objective - Mice null for both apolipoprotein (apo)E and scavenger receptor (SR)-BI (DKO) develop severe hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarction, and premature death. The current study examines the ability of macrophage apoE to improve the dyslipidemia, reduce atherosclerosis, and rescue the lethal phenotype of DKO mice. Methods and Results - Initially, bone marrow transplantation (BMT) was unsuccessful, because the DKO mice died from a rapidly fatal anemia 3 to 5 days after lethal irradiation. Therefore, probucol was used to rescue the DKO mice during BMT and was discontinued 2-weeks after BMT, allowing successful reconstitution with donor marrow. Twelve male apoE-/-SR-BI-/- mice fed 0.5% probucol in a chow diet were lethally irradiated and transplanted with either wild-type (WT) or DKO bone marrow. Two-weeks after BMT, apoE was detected in serum in WT→DKO mice, and mean serum cholesterol levels were reduced by 70% versus DKO→DKO mice. Lipoprotein profiles and HDL subpopulations in WT→DKO mice were similar to apoE-/+SR-BI-/-→DKO mice and resembled those of SR-BI-/- mice. In WT→DKO mice, aortic atherosclerosis was reduced by 88% to 90% versus DKO→DKO mice. Furthermore, the DKO→DKO mice died ≈8 weeks after BMT, whereas WT→DKO mice exhibited a life span >40 weeks after BMT. Conclusions - Macrophage apoE is able to rescue the lethal phenotype of apoE -/-SR-BI-/- mice by improving the dyslipidemia and dramatically reducing atherosclerotic lesion development.

Original languageEnglish (US)
Pages (from-to)150-156
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume26
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

Fingerprint

Low Density Lipoprotein Receptor-Related Protein-1
Scavenger Receptors
Premature Mortality
Apolipoproteins E
Knockout Mice
Atherosclerosis
Macrophages
Bone Marrow Transplantation
Probucol
Dyslipidemias
Bone Marrow
Phenotype

Keywords

  • Apolipoprotein E
  • Atherosclerosis
  • Cholesterol
  • Macrophages
  • SR-BI

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Macrophage apolipoprotein E reduces atherosclerosis and prevents premature death in apolipoprotein E and scavenger receptor-class BI double-knockout mice. / Yu, Hong; Zhang, Wenwu; Yancey, Patricia G.; Koury, Mark J.; Zhang, Youmin; Fazio, Sergio; Linton, MacRae F.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 26, No. 1, 01.2006, p. 150-156.

Research output: Contribution to journalArticle

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abstract = "Objective - Mice null for both apolipoprotein (apo)E and scavenger receptor (SR)-BI (DKO) develop severe hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarction, and premature death. The current study examines the ability of macrophage apoE to improve the dyslipidemia, reduce atherosclerosis, and rescue the lethal phenotype of DKO mice. Methods and Results - Initially, bone marrow transplantation (BMT) was unsuccessful, because the DKO mice died from a rapidly fatal anemia 3 to 5 days after lethal irradiation. Therefore, probucol was used to rescue the DKO mice during BMT and was discontinued 2-weeks after BMT, allowing successful reconstitution with donor marrow. Twelve male apoE-/-SR-BI-/- mice fed 0.5{\%} probucol in a chow diet were lethally irradiated and transplanted with either wild-type (WT) or DKO bone marrow. Two-weeks after BMT, apoE was detected in serum in WT→DKO mice, and mean serum cholesterol levels were reduced by 70{\%} versus DKO→DKO mice. Lipoprotein profiles and HDL subpopulations in WT→DKO mice were similar to apoE-/+SR-BI-/-→DKO mice and resembled those of SR-BI-/- mice. In WT→DKO mice, aortic atherosclerosis was reduced by 88{\%} to 90{\%} versus DKO→DKO mice. Furthermore, the DKO→DKO mice died ≈8 weeks after BMT, whereas WT→DKO mice exhibited a life span >40 weeks after BMT. Conclusions - Macrophage apoE is able to rescue the lethal phenotype of apoE -/-SR-BI-/- mice by improving the dyslipidemia and dramatically reducing atherosclerotic lesion development.",
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AU - Zhang, Wenwu

AU - Yancey, Patricia G.

AU - Koury, Mark J.

AU - Zhang, Youmin

AU - Fazio, Sergio

AU - Linton, MacRae F.

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AB - Objective - Mice null for both apolipoprotein (apo)E and scavenger receptor (SR)-BI (DKO) develop severe hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarction, and premature death. The current study examines the ability of macrophage apoE to improve the dyslipidemia, reduce atherosclerosis, and rescue the lethal phenotype of DKO mice. Methods and Results - Initially, bone marrow transplantation (BMT) was unsuccessful, because the DKO mice died from a rapidly fatal anemia 3 to 5 days after lethal irradiation. Therefore, probucol was used to rescue the DKO mice during BMT and was discontinued 2-weeks after BMT, allowing successful reconstitution with donor marrow. Twelve male apoE-/-SR-BI-/- mice fed 0.5% probucol in a chow diet were lethally irradiated and transplanted with either wild-type (WT) or DKO bone marrow. Two-weeks after BMT, apoE was detected in serum in WT→DKO mice, and mean serum cholesterol levels were reduced by 70% versus DKO→DKO mice. Lipoprotein profiles and HDL subpopulations in WT→DKO mice were similar to apoE-/+SR-BI-/-→DKO mice and resembled those of SR-BI-/- mice. In WT→DKO mice, aortic atherosclerosis was reduced by 88% to 90% versus DKO→DKO mice. Furthermore, the DKO→DKO mice died ≈8 weeks after BMT, whereas WT→DKO mice exhibited a life span >40 weeks after BMT. Conclusions - Macrophage apoE is able to rescue the lethal phenotype of apoE -/-SR-BI-/- mice by improving the dyslipidemia and dramatically reducing atherosclerotic lesion development.

KW - Apolipoprotein E

KW - Atherosclerosis

KW - Cholesterol

KW - Macrophages

KW - SR-BI

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