Inactivation of macrophage scavenger receptor class B type I promotes atherosclerotic lesion development in apolipoprotein E-deficient mice.
BACKGROUND
Scavenger receptor class B type I (SR-BI) is expressed in macrophages, where it has been proposed to facilitate cholesterol efflux. However, direct evidence that the expression of macrophage SR-BI is protective against atherosclerosis is lacking. In this study, we examined the in vivo role of macrophage SR-BI in atherosclerotic lesion development in the apolipoprotein (apo) E-deficient mouse model.


RESULTS
ApoE-deficient mice with (n=16) or without (n=15) expression of macrophage SR-BI were created by transplanting lethally irradiated apoE-deficient mice with bone marrow cells collected from SR-BI-/- apoE-/- mice or SR-BI+/+ apoE-/- mice. The recipient mice were fed a chow diet for 12 weeks after transplantation for analysis of atherosclerosis. Quantification of macrophage SR-BI mRNA by real-time reverse transcription-polymerase chain reaction indicated successful engraftment of donor bone marrow and inactivation of macrophage SR-BI in recipient mice reconstituted with SR-BI-/- apoE-/- bone marrow. There were no significant differences in plasma lipid levels, lipoprotein distributions, and HDL subpopulations between the 2 groups. Analysis of the proximal aorta demonstrated an 86% increase in mean atherosclerotic lesion area in SR-BI-/- apoE-/- --> apoE-/- mice compared with SR-BI+/+ apoE-/- --> apoE-/- mice (109.50+/-18.08 versus 58.75+/-9.58x10(3) microm2; mean+/-SEM, P=0.017). No difference in cholesterol efflux from SR-BI+/+ apoE-/- or SR-BI-/- apoE-/- macrophages to HDL or apoA-I discs was detected.


CONCLUSIONS
Expression of macrophage SR-BI protects mice against atherosclerotic lesion development in apoE-deficient mice in vivo without influencing plasma lipids, HDL subpopulations, or cholesterol efflux. Thus, macrophage SR-BI plays an antiatherogenic role in vivo, providing a new therapeutic target for the design of strategies to prevent and treat atherosclerosis.
Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Departments of Medicine, Vanderbilt University Medical Center, Nashville, Tenn 37232-6300, USA.
Wenwu
W
Zhang
Patricia G
PG
Yancey
Yan Ru
YR
Su
Vladimir R
VR
Babaev
Yuomin
Y
Zhang
Sergio
S
Fazio
MacRae F
MF
Linton
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000235:genetics / Q000473:pathology*; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D018955:CD36 Antigens / Q000096:biosynthesis / Q000235:genetics*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D008075:Lipoproteins, HDL / Q000097:blood; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011828:Radiation Chimera; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D018955:CD36 Antigens; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D002784:Cholesterol