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Cardiovascular Research 2007 76(1):175-183; doi:10.1016/j.cardiores.2007.05.016
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Copyright © 2007, European Society of Cardiology

Bone marrow-derived multidrug resistance protein ABCB4 protects against atherosclerotic lesion development in LDL receptor knockout mice

Marieke Penningsa,*, Reeni B. Hildebranda, Dan Yea, Cindy Kunneb, Theo J.C. Van Berkela, Albert K. Groenb and Miranda Van Ecka

aDivision of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands
bDepartment of Medical Biochemistry, Amsterdam Medical Center, Meibergdreef 15, 1105 BK Amsterdam, The Netherlands

,*Corresponding author. Einsteinweg 55, 2333 CC Leiden, The Netherlands. Tel.: +31 715276213; fax: + 31 715276032. pennings{at}lacdr.leidenuniv.nl

Objective Several members of the ATP binding cassette (ABC)-transporter super family expressed in macrophages protect against atherosclerosis by promoting macrophage cholesterol and phospholipid efflux. Systemic disruption of ABCB4 in mice results in a virtual absence of phospholipids in bile and a strongly impaired biliary cholesterol secretion, indicating that ABCB4 plays an essential role in cellular lipid efflux. The aim of the current study was to determine the role of bone marrow-derived ABCB4 in atherosclerotic lesion development.

Methods Chimeras were created that specifically lack ABCB4 in bone marrow-derived cells, including macrophages, by performing a bone marrow transplantation on LDL receptor knockout (LDLr–/–) mice. Atherosclerotic lesion development was induced by feeding a high-cholesterol diet (15% fat and 0.25% cholesterol).

Results Serum cholesterol levels were significantly lower in mice reconstituted with ABCB4 knockout bone marrow as a result of reduced VLDL and LDL cholesterol levels. Despite the lower serum cholesterol levels, ABCB4 deficiency in bone marrow-derived cells resulted in a 1.8-fold (p=0.005) increase in lesion size. In vitro foam cell formation, induced with acetylated LDL (AcLDL) in peritoneal macrophages, was increased in the absence of ABCB4, possibly due to a 2-fold (p<0.05) increased association of AcLDL, while the efflux of cholesterol was unaffected.

Conclusion Bone marrow-derived ABCB4 has an important anti-atherosclerotic function, probably by limiting macrophage foam cell formation.

KEYWORDS Atherosclerosis; Cholesterol; Lipid metabolism; Macrophages; Membrane transport; Phospholipids; ATP-binding cassette transporters; ABCB4; Multidrug resistance; Bone marrow transplantation

* This work was supported by The Netherlands Organisation of Scientific Research (grant 912-02-063 and VIDI grant 917-66-301) and The Netherlands Heart Foundation (grant 2001T041).


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