Relationship between Expression Levels and Atherogenesis in Scavenger Receptor Class B, Type I Transgenics

• Published in: The Journal of biological chemistry Vol. 275; no. 27; pp. 20368 - 20373
• Main Authors: Ueda, Yukihiko, Gong, Elaine, Royer, Lori, Cooper, Philip N., Francone, Omar L., Rubin, Edward M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.07.2000; American Society for Biochemistry and Molecular Biology
• Subjects: ANIMALS; Aorta - pathology; apolipoprotein B; Apolipoproteins B - blood; Apolipoproteins B - genetics; Arteriosclerosis - blood; Arteriosclerosis - genetics; ATHEROGENESIS; BASIC BIOLOGICAL SCIENCES; CD36 Antigens - blood; CD36 Antigens - genetics; CHOLESTEROL; Cholesterol, HDL - blood; Diet, Atherogenic; ELECTROPHORESIS; Electrophoresis, Gel, Two-Dimensional; Female; Gene Expression Regulation - genetics; HDL CHOLESTEROL; Histocytochemistry; Humans; HYPOTHESIS; IN VITRO; IN VIVO; Lipids - blood; LIPOPROTEINS; Lipoproteins, HDL - blood; Liver - metabolism; Membrane Proteins; METABOLISM; MICE; Mice, Transgenic; Myocardium - pathology; Receptors, Immunologic; Receptors, LDL - genetics; Receptors, Lipoprotein; Receptors, Scavenger; Ribonucleases - metabolism; scavenger receptors; Scavenger Receptors, Class B; SR-BI; TRANSGENIC MICE
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M000730200

Both in vitro and in vivostudies of scavenger receptor class B type I (SR-BI) have implicated it as a likely participant in the metabolism of HDL cholesterol. To investigate the effect of SR-BI on atherogenesis, we examined two lines of SR-BI transgenic mice with high (10-fold increases) and low (2-fold increases) SR-BI expression in an inbred mouse background hemizygous for a human apolipoprotein (apo) B transgene. Unlike non-HDL cholesterol levels that minimally differed in the various groups of animals, HDL cholesterol levels were inversely related to SR-BI expression. Mice with the low expression SR-BI transgene had a 50% reduction in HDL cholesterol, whereas the high expression SR-BI transgene was associated with 2-fold decreases in HDL cholesterol as well as dramatic alterations in HDL composition and size including the near absence of α-migrating particles as determined by two-dimensional electrophoresis. The low expression SR-BI/apo B transgenics had more than a 2-fold decrease in the development of diet-induced fatty streak lesions compared with the apo B transgenics (4448 ± 1908 μm2/aorta to 10133 ± 4035 μm2/aorta; p < 0.001), whereas the high expression SR-BI/apo B transgenics had an atherogenic response similar to that of the apo B transgenics (14692 ± 7238 μm2/aorta) but 3-fold greater than the low SR-BI/apo B mice (p < 0.001). The prominent anti-atherogenic effect of moderate SR-BI expression provides in vivosupport for the hypothesis that HDL functions to inhibit atherogenesis through its interactions with SR-BI in facilitating reverse cholesterol transport. The failure of the high SR-BI/apo B transgenics to have similar or even greater reductions in atherogenesis suggests that the changes resulting from extremely high SR-BI expression including dramatic changes in lipoproteins may have both pro- and anti-atherogenic consequences, illustrating the complexity of the relationship between SR-BI and atherogenesis.