Relationship between expression levels and atherogenesis in scavenger receptor class B, type I transgenics

Both in vitro and in vivo studies of scavenger receptor class B type I (SR- BT) have implicated it as a likely participant in the metabolism of HDL cho lesterol, 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 le vels that minimally differed in the various groups of animals, HDL choleste rol levels were inversely related to SR-BI expression. Mice with the low ex pression SR-BI transgene had a 50% reduction in HDL cholesterol, whereas th e high expression SR-BI transgene was associated with 2-fold decreases in H DL cholesterol as well as dramatic alterations in HDL composition and size including the near absence of alpha-migrating particles as determined by tw o-dimensional electrophoresis. The low expression SR-BI/apo B transgenics h ad more than a 2-fold decrease in the development of diet-induced fatty str eak lesions compared with the apo B transgenics (4448 +/- 1908 mu m(2)/aort a to 10133 +/- 4035 mu m(2)/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 mu m(2)/aorta) but 3-fold greater than th e low SR-BI/apo E mice (p < 0.001), The prominent anti-atherogenic effect o f moderate SR-BI expression provides in vivo support for the hypothesis tha t HDL functions to inhibit atherogenesis through its interactions with SR-B I in facilitating reverse cholesterol transport. The failure of the high SR -BI/apo B transgenics to have similar or even greater reductions in atherog enesis suggests that the changes resulting from extremely high SR-BI expres sion including dramatic changes in lipoproteins may have both pro- and anti -atherogenic consequences, illustrating the complexity of the relationship between SR-BI and atherogenesis.