TY - JOUR
T1 - Bone marrow-derived multidrug resistance protein ABCB4 protects against atherosclerotic lesion development in LDL receptor knockout mice
AU - Pennings, Marieke
AU - Hildebrand, Reeni B.
AU - Ye, Dan
AU - Kunne, Cindy
AU - van Berkel, Theo J. C.
AU - Groen, Albert K.
AU - van Eck, Miranda
PY - 2007
Y1 - 2007
N2 - 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
AB - 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
U2 - https://doi.org/10.1016/j.cardiores.2007.05.016
DO - https://doi.org/10.1016/j.cardiores.2007.05.016
M3 - Article
C2 - 17560559
SN - 0008-6363
VL - 76
SP - 175
EP - 183
JO - Cardiovascular research
JF - Cardiovascular research
IS - 1
ER -