The combined role of P- and E-selectins 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 bred P- and E-selectin-double-deficient mice onto the low-density lipoprotein receptor (LDLR)-deficient background (LDLR-/- P/E-/-) and compared lesion development in these mice to that in mice wild type for both 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 macrophages in the fatty streaks was comparable between LDLR-/- P/E+/+ and LDLR-/- P/E-/- mice. After 22 wk on the diet, the lesions spread throughout the aorta but this process was delayed in LDLR-/- P/E-/- mice. At 37 wk on diet, the lesions progressed to the fibrous plaque stage 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 atherosclerotic lesion development.
Dong
Z M
ZM
Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115, USA.
Chapman
S M
SM
Brown
A A
AA
Frenette
P S
PS
Hynes
R O
RO
Wagner
D D
DD
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology* / Q000473:pathology; D019040:E-Selectin / Q000502:physiology*; D005260:Female; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019007:P-Selectin / Q000502:physiology*; D011973:Receptors, LDL / Q000172:deficiency / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis
D019040:E-Selectin; D008077:Lipoproteins, LDL; D019007:P-Selectin; D011973:Receptors, LDL; D019010:Vascular Cell Adhesion Molecule-1; C099252:oxidized low density lipoprotein