COMBINED ROLE OF P-SELECTIN AND E-SELECTIN IN ATHEROSCLEROSIS

P- and E-selectins are adhesion molecules mediating the first step in leukocyte extravasation. Because their function in leukocyte adhesion is overlapping, we hypothesized that there might be a combined effect of these selectins on the development of atherosclerotic lesions. We b red P- and E-selectin-double-deficient mice onto the low-density lipop rotein receptor (LDLR)-deficient background (LDLR-/- P/E-/-) and compa red lesion development in these mice to that in mice wild type for bot h selectins (LDLR-/- P/E+/+), After 8 wk on atherogenic diet, the LDLR -/- P/E-/- mice developed fatty streaks in the aortic sinus that were five times smaller than those in LDLR-/- P/E+/+ mice. The density of m acrophages in the fatty streaks was comparable between LDLR-/- P/E+/and LDLR-/- P/E-/- mice. After 22 wk on the diet, the lesions spread t hroughout the aorta but this process was delayed in LDLR-/- P/E-/- mic e. At 37 wk on diet, the lesions progressed to the fibrous plaque stag e in both genotypes, However, the lesions in the aortic sinus in LDLR- /- P/E-/- mice were 40% smaller and less calcified than those of LDLR- /- P/E +/+ mice. Our results suggest that P- and E-selectins together play an important role in both early and advanced stages of atheroscle rotic lesion development.