Effect of human scavenger receptor class A overexpression in bone marrow-derived cells on cholesterol levels and atherosclerosis in ApoE-deficient mice.
In the arterial wall, scavenger receptor class A (SRA) is implicated in pathological lipid deposition. In contrast, in the liver, SRA is suggested to remove modified lipoproteins from the circulation, thereby protecting the body from their pathological action. The role of SRA on bone marrow-derived cells in lipid metabolism and atherogenesis was assessed in vivo by transplantation of bone marrow cells overexpressing human SRA (MSR1) to apoE-deficient mice. In vitro studies with peritoneal macrophages from the transplanted mice showed that macrophage scavenger receptor function, as measured by cell association and degradation studies with acetylated LDL, was approximately 3-fold increased on overexpression of MSR1 in bone marrow-derived cells as compared with control mice. Despite the increased macrophage scavenger receptor function in vitro, no significant effect of MSR1 overexpression in bone marrow-derived cells on the in vivo atherosclerotic lesion development was found. In addition to arterial wall macrophages, liver sinusoidal Kupffer cells also overexpress MSR1 after bone marrow transplantation, which may scavenge atherogenic particles more efficiently from the blood compartment. Introduction of bone marrow cells overexpressing human MSR1 in apoE-deficient mice induced a significant reduction in serum cholesterol levels of approximately 20% (P:<0.001, 2-way ANOVA) as the result of a decrease in VLDL cholesterol. It is suggested that the reduction in VLDL cholesterol levels is due to increased clearance of modified lipoproteins by the overexpressed MSR1 in Kupffer cells of the liver, thereby protecting the arterial wall against the proatherogenic action of modified lipoproteins.
Van Eck
M
M
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University Medical Center, Sylvius Laboratories, Leiden University (The Netherlands). M.Eck@LACDR.LeidenUniv.nl
De Winther
M P
MP
Herijgers
N
N
Havekes
L M
LM
Hofker
M H
MH
Groot
P H
PH
Van Berkel
T J
TJ
D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000097:blood / Q000209:etiology* / Q000235:genetics; D001854:Bone Marrow Cells / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D015243:Cholesterol, VLDL / Q000097:blood; D005260:Female; D006801:Humans; D007728:Kupffer Cells / Q000378:metabolism; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000235:genetics; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; D014280:Triglycerides / Q000097:blood; D014916:Whole-Body Irradiation
D001057:Apolipoproteins E; D015243:Cholesterol, VLDL; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; D014280:Triglycerides; C032629:acetyl-LDL; C099252:oxidized low density lipoprotein