DEFICIENCY OF INFLAMMATORY CELL-ADHESION MOLECULES PROTECTS AGAINST ATHEROSCLEROSIS IN MICE

Leukocyte and endothelial cell adhesion molecules (CAMs) are essential for emigration of leukocytes, with the selectins mediating the initia l step of leukocyte ''rolling'' and the beta(2)-(CD18) integrins and i ntercellular adhesion molecule-1 (ICAM-1) being important for firm adh esion and emigration. On the basis of evidence for an inflammatory com ponent in the pathogenesis of atherosclerosis, including increased exp ression of CAMs, cytokines, and growth factors, we tested the hypothes is that decreased expression of inflammatory CAMs would reduce suscept ibility to atherosclerosis. Using C57BL/6 mice fed a high-fat diet, we observed a 50% to 75% reduction in atherosclerotic fatty streaks in m ice with homozygous mutations for ICAM-1, P-selectin, CD18, both ICAM- 1 and CD18, or both ICAM-1 and P-selectin. In contrast to previous evi dence of increased expression of CAMs in atherosclerotic lesions, whic h does not prove a cause-and-effect relationship, these data indicate directly that the level of expression of CAMs can determine the suscep tibility to the formation of atherosclerotic fatty streaks. The result s suggest that genetic variation at these loci could influence suscept ibility to atherosclerosis and that pharmacological reduction of the e xpression or function of these CAMs might protect against atherosclero sis.