Enhanced Foam Cell Formation, Atherosclerotic Lesion Development, and Inflammation by Combined Deletion of ABCA1 and SR-BI in Bone Marrow-Derived Cells in LDL Receptor Knockout Mice on Western-Type Diet

Ying Zhao; Marieke Pennings; Reeni B. Hildebrand; Dan Ye; Laura Calpe-Berdiel; Ruud Out; Martin Kjerrulf; Eva Hurt-Camejo; Albert K. Groen; Menno Hoekstra; Wendy Jessup; Giovanna Chimini; Theo J. C. Van Berkel; Miranda Van Eck

doi:10.1161/CIRCRESAHA.110.226282

Enhanced Foam Cell Formation, Atherosclerotic Lesion Development, and Inflammation by Combined Deletion of ABCA1 and SR-BI in Bone Marrow-Derived Cells in LDL Receptor Knockout Mice on Western-Type Diet

Ying Zhao, Marieke Pennings, Reeni B. Hildebrand, Dan Ye, Laura Calpe-Berdiel, Ruud Out, Martin Kjerrulf, Eva Hurt-Camejo, Albert K. Groen, Menno Hoekstra, Wendy Jessup, Giovanna Chimini, Theo J. C. Van Berkel, Miranda Van Eck^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Rationale: Macrophages cannot limit the uptake of lipids and rely on cholesterol efflux mechanisms for maintaining cellular cholesterol homeostasis. Important mediators of macrophage cholesterol efflux are ATP-binding cassette transporter 1 (ABCA1), which mediates the efflux of cholesterol to lipid-poor apolipoprotein AI, and scavenger receptor class B type I (SR-BI), which promotes efflux to mature high-density lipoprotein.

Objective: The aim of the present study was to increase the insight into the putative synergistic roles of ABCA1 and SR-BI in foam cell formation and atherosclerosis.

Methods and Results: Low-density lipoprotein receptor knockout (LDLr KO) mice were transplanted with bone marrow from ABCA1/SR-BI double knockout mice, the respective single knockouts, or wild-type littermates. Serum cholesterol levels were lower in ABCA1/SR-BI double knockout transplanted animals, as compared to the single knockout and wild-type transplanted animals on Western-type diet. Despite the lower serum cholesterol levels, massive foam cell formation was found in macrophages from spleen and the peritoneal cavity. Interestingly, ABCA1/SR-BI double knockout transplanted animals also showed a major increase in proinflammatory KC (murine interleukin-8) and interleukin-12p40 levels in the circulation. Furthermore, after 10 weeks of Western-type diet feeding, atherosclerotic lesion development in the aortic root was more extensive in the LDLr KO mice reconstituted with ABCA1/SR-BI double knockout bone marrow.

Conclusions: Deletion of ABCA1 and SR-BI in bone marrow-derived cells enhances in vivo macrophage foam cell formation and atherosclerotic lesion development in LDLr KO mice on Western diet, indicating that under high dietary lipid conditions, both macrophage ABCA1 and SR-BI contribute significantly to cholesterol homeostasis in the macrophage in vivo and are essential for reducing the risk for atherosclerosis. (Circ Res. 2010; 107: e20-e31.)

Original language	English
Pages (from-to)	E20-+
Number of pages	19
Journal	Circulation Research
Volume	107
Issue number	12
DOIs	https://doi.org/10.1161/CIRCRESAHA.110.226282
Publication status	Published - 10-Dec-2010

Keywords

atherosclerosis
cholesterol
cytokines
macrophages
neutrophils
REVERSE CHOLESTEROL TRANSPORT
E-DEFICIENT MICE
BINDING CASSETTE TRANSPORTERS
CORONARY-ARTERY-DISEASE
LIPID-ACCUMULATION
MACROPHAGE ABCA1
IN-VIVO
A-I
ABCG1
EXPRESSION

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Zhao, Y., Pennings, M., Hildebrand, R. B., Ye, D., Calpe-Berdiel, L., Out, R., Kjerrulf, M., Hurt-Camejo, E., Groen, A. K., Hoekstra, M., Jessup, W., Chimini, G., Van Berkel, T. J. C., & Van Eck, M. (2010). Enhanced Foam Cell Formation, Atherosclerotic Lesion Development, and Inflammation by Combined Deletion of ABCA1 and SR-BI in Bone Marrow-Derived Cells in LDL Receptor Knockout Mice on Western-Type Diet. Circulation Research, 107(12), E20-+. https://doi.org/10.1161/CIRCRESAHA.110.226282

@article{d1bf866dfec64450b773bc98894d8010,

title = "Enhanced Foam Cell Formation, Atherosclerotic Lesion Development, and Inflammation by Combined Deletion of ABCA1 and SR-BI in Bone Marrow-Derived Cells in LDL Receptor Knockout Mice on Western-Type Diet",

abstract = "Rationale: Macrophages cannot limit the uptake of lipids and rely on cholesterol efflux mechanisms for maintaining cellular cholesterol homeostasis. Important mediators of macrophage cholesterol efflux are ATP-binding cassette transporter 1 (ABCA1), which mediates the efflux of cholesterol to lipid-poor apolipoprotein AI, and scavenger receptor class B type I (SR-BI), which promotes efflux to mature high-density lipoprotein.Objective: The aim of the present study was to increase the insight into the putative synergistic roles of ABCA1 and SR-BI in foam cell formation and atherosclerosis.Methods and Results: Low-density lipoprotein receptor knockout (LDLr KO) mice were transplanted with bone marrow from ABCA1/SR-BI double knockout mice, the respective single knockouts, or wild-type littermates. Serum cholesterol levels were lower in ABCA1/SR-BI double knockout transplanted animals, as compared to the single knockout and wild-type transplanted animals on Western-type diet. Despite the lower serum cholesterol levels, massive foam cell formation was found in macrophages from spleen and the peritoneal cavity. Interestingly, ABCA1/SR-BI double knockout transplanted animals also showed a major increase in proinflammatory KC (murine interleukin-8) and interleukin-12p40 levels in the circulation. Furthermore, after 10 weeks of Western-type diet feeding, atherosclerotic lesion development in the aortic root was more extensive in the LDLr KO mice reconstituted with ABCA1/SR-BI double knockout bone marrow.Conclusions: Deletion of ABCA1 and SR-BI in bone marrow-derived cells enhances in vivo macrophage foam cell formation and atherosclerotic lesion development in LDLr KO mice on Western diet, indicating that under high dietary lipid conditions, both macrophage ABCA1 and SR-BI contribute significantly to cholesterol homeostasis in the macrophage in vivo and are essential for reducing the risk for atherosclerosis. (Circ Res. 2010; 107: e20-e31.)",

keywords = "atherosclerosis, cholesterol, cytokines, macrophages, neutrophils, REVERSE CHOLESTEROL TRANSPORT, E-DEFICIENT MICE, BINDING CASSETTE TRANSPORTERS, CORONARY-ARTERY-DISEASE, LIPID-ACCUMULATION, MACROPHAGE ABCA1, IN-VIVO, A-I, ABCG1, EXPRESSION",

author = "Ying Zhao and Marieke Pennings and Hildebrand, {Reeni B.} and Dan Ye and Laura Calpe-Berdiel and Ruud Out and Martin Kjerrulf and Eva Hurt-Camejo and Groen, {Albert K.} and Menno Hoekstra and Wendy Jessup and Giovanna Chimini and {Van Berkel}, {Theo J. C.} and {Van Eck}, Miranda",

year = "2010",

month = dec,

day = "10",

doi = "10.1161/CIRCRESAHA.110.226282",

language = "English",

volume = "107",

pages = "E20--+",

journal = "Circulation Research",

issn = "0009-7330",

publisher = "Lippincott Williams and Wilkins",

number = "12",

}

Zhao, Y, Pennings, M, Hildebrand, RB, Ye, D, Calpe-Berdiel, L, Out, R, Kjerrulf, M, Hurt-Camejo, E, Groen, AK, Hoekstra, M, Jessup, W, Chimini, G, Van Berkel, TJC & Van Eck, M 2010, 'Enhanced Foam Cell Formation, Atherosclerotic Lesion Development, and Inflammation by Combined Deletion of ABCA1 and SR-BI in Bone Marrow-Derived Cells in LDL Receptor Knockout Mice on Western-Type Diet', Circulation Research, vol. 107, no. 12, pp. E20-+. https://doi.org/10.1161/CIRCRESAHA.110.226282

Enhanced Foam Cell Formation, Atherosclerotic Lesion Development, and Inflammation by Combined Deletion of ABCA1 and SR-BI in Bone Marrow-Derived Cells in LDL Receptor Knockout Mice on Western-Type Diet. / Zhao, Ying; Pennings, Marieke; Hildebrand, Reeni B. et al.
In: Circulation Research, Vol. 107, No. 12, 10.12.2010, p. E20-+.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Enhanced Foam Cell Formation, Atherosclerotic Lesion Development, and Inflammation by Combined Deletion of ABCA1 and SR-BI in Bone Marrow-Derived Cells in LDL Receptor Knockout Mice on Western-Type Diet

AU - Zhao, Ying

AU - Pennings, Marieke

AU - Hildebrand, Reeni B.

AU - Ye, Dan

AU - Calpe-Berdiel, Laura

AU - Out, Ruud

AU - Kjerrulf, Martin

AU - Hurt-Camejo, Eva

AU - Groen, Albert K.

AU - Hoekstra, Menno

AU - Jessup, Wendy

AU - Chimini, Giovanna

AU - Van Berkel, Theo J. C.

AU - Van Eck, Miranda

PY - 2010/12/10

Y1 - 2010/12/10

N2 - Rationale: Macrophages cannot limit the uptake of lipids and rely on cholesterol efflux mechanisms for maintaining cellular cholesterol homeostasis. Important mediators of macrophage cholesterol efflux are ATP-binding cassette transporter 1 (ABCA1), which mediates the efflux of cholesterol to lipid-poor apolipoprotein AI, and scavenger receptor class B type I (SR-BI), which promotes efflux to mature high-density lipoprotein.Objective: The aim of the present study was to increase the insight into the putative synergistic roles of ABCA1 and SR-BI in foam cell formation and atherosclerosis.Methods and Results: Low-density lipoprotein receptor knockout (LDLr KO) mice were transplanted with bone marrow from ABCA1/SR-BI double knockout mice, the respective single knockouts, or wild-type littermates. Serum cholesterol levels were lower in ABCA1/SR-BI double knockout transplanted animals, as compared to the single knockout and wild-type transplanted animals on Western-type diet. Despite the lower serum cholesterol levels, massive foam cell formation was found in macrophages from spleen and the peritoneal cavity. Interestingly, ABCA1/SR-BI double knockout transplanted animals also showed a major increase in proinflammatory KC (murine interleukin-8) and interleukin-12p40 levels in the circulation. Furthermore, after 10 weeks of Western-type diet feeding, atherosclerotic lesion development in the aortic root was more extensive in the LDLr KO mice reconstituted with ABCA1/SR-BI double knockout bone marrow.Conclusions: Deletion of ABCA1 and SR-BI in bone marrow-derived cells enhances in vivo macrophage foam cell formation and atherosclerotic lesion development in LDLr KO mice on Western diet, indicating that under high dietary lipid conditions, both macrophage ABCA1 and SR-BI contribute significantly to cholesterol homeostasis in the macrophage in vivo and are essential for reducing the risk for atherosclerosis. (Circ Res. 2010; 107: e20-e31.)

AB - Rationale: Macrophages cannot limit the uptake of lipids and rely on cholesterol efflux mechanisms for maintaining cellular cholesterol homeostasis. Important mediators of macrophage cholesterol efflux are ATP-binding cassette transporter 1 (ABCA1), which mediates the efflux of cholesterol to lipid-poor apolipoprotein AI, and scavenger receptor class B type I (SR-BI), which promotes efflux to mature high-density lipoprotein.Objective: The aim of the present study was to increase the insight into the putative synergistic roles of ABCA1 and SR-BI in foam cell formation and atherosclerosis.Methods and Results: Low-density lipoprotein receptor knockout (LDLr KO) mice were transplanted with bone marrow from ABCA1/SR-BI double knockout mice, the respective single knockouts, or wild-type littermates. Serum cholesterol levels were lower in ABCA1/SR-BI double knockout transplanted animals, as compared to the single knockout and wild-type transplanted animals on Western-type diet. Despite the lower serum cholesterol levels, massive foam cell formation was found in macrophages from spleen and the peritoneal cavity. Interestingly, ABCA1/SR-BI double knockout transplanted animals also showed a major increase in proinflammatory KC (murine interleukin-8) and interleukin-12p40 levels in the circulation. Furthermore, after 10 weeks of Western-type diet feeding, atherosclerotic lesion development in the aortic root was more extensive in the LDLr KO mice reconstituted with ABCA1/SR-BI double knockout bone marrow.Conclusions: Deletion of ABCA1 and SR-BI in bone marrow-derived cells enhances in vivo macrophage foam cell formation and atherosclerotic lesion development in LDLr KO mice on Western diet, indicating that under high dietary lipid conditions, both macrophage ABCA1 and SR-BI contribute significantly to cholesterol homeostasis in the macrophage in vivo and are essential for reducing the risk for atherosclerosis. (Circ Res. 2010; 107: e20-e31.)

KW - atherosclerosis

KW - cholesterol

KW - cytokines

KW - macrophages

KW - neutrophils

KW - REVERSE CHOLESTEROL TRANSPORT

KW - E-DEFICIENT MICE

KW - BINDING CASSETTE TRANSPORTERS

KW - CORONARY-ARTERY-DISEASE

KW - LIPID-ACCUMULATION

KW - MACROPHAGE ABCA1

KW - IN-VIVO

KW - A-I

KW - ABCG1

KW - EXPRESSION

U2 - 10.1161/CIRCRESAHA.110.226282

DO - 10.1161/CIRCRESAHA.110.226282

M3 - Article

SN - 0009-7330

VL - 107

SP - E20-+

JO - Circulation Research

JF - Circulation Research

IS - 12

ER -

Enhanced Foam Cell Formation, Atherosclerotic Lesion Development, and Inflammation by Combined Deletion of ABCA1 and SR-BI in Bone Marrow-Derived Cells in LDL Receptor Knockout Mice on Western-Type Diet

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Keywords

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