Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1068-1073
© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Increased LDL Cholesterol and Atherosclerosis in LDL Receptor–Deficient Mice With Attenuated Expression of Scavenger Receptor B1
From Millennium Pharmaceuticals, Inc (D.H., M.L.V., R.F., V.F.-H., M.J.D.), Cambridge, Mass; the Division of Molecular Medicine (F.R., T.A., A.R.T.), Department of Medicine, Columbia University, New York, NY; and Universitat Hamburg (F.R.), Krankenhaus Eppendorf, Medizinische Klinik, Hamburg, Germany.
Correspondence to Dennis Huszar, Millennium Pharmaceuticals, Inc, 75 Sidney St, Cambridge, MA 02139. E-mail huszar{at}mpi.com
Abstract—Scavenger receptor BI (SR-BI) is a multiligand cell-surface receptor that plays a central role in high density lipoprotein homeostasis in rodents. To investigate a role for SR-BI in atherosclerosis, mice with attenuated SR-BI expression were crossed with low density lipoprotein (LDL) receptor–deficient mice. Compound-homozygous mutants showed increased plasma cholesterol, surprisingly due primarily to increased LDL cholesterol and apolipoprotein B levels. LDL turnover studies showed that this resulted from increased LDL cholesterol production rather than decreased LDL catabolism. Atherosclerotic lesion size was significantly increased in male compound-mutant mice relative to LDL receptor–deficient controls (93 427±16 079 versus 34 448±5 331 µm2, respectively; P=0.003). The proatherogenic effect of attenuated SR-BI expression may in part be due to increased LDL cholesterol levels. These findings suggest that upregulation of the receptor could have therapeutic potential for the treatment of atherosclerosis.
Key Words: scavenger receptor BI • atherosclerosis • HDL • cholesterol • mouse
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