P-selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice

The expression of leukocyte and endothelial cell adhesion molecules (CAMs) is essential for the emigration of leukocytes during an inflammatory respon se. The importance of the inflammatory response in the development of ather osclerosis is indicated by the increased expression of adhesion molecules, proinflammatory cytokines, and growth factors in lesions and lesion-prone a reas and by protection in mice deficient in various aspects of the inflamma tory response. We have quantitated the effect of deficiency for intercellul ar adhesion molecule (ICAM)-1, P-selectin, or E-selectin on atherosclerotic lesion formation at 20 wk of age in apolipoprotein (apo) E-/- (deficient) mice fed a normal chow diet. All mice were apo E-/- and CAM(+/+) or CAM(-/- ) littermates, and no differences were found in body weight or cholesterol levels among the various genotypes during the: study. ICAM-1(-/-) mice had significantly less lesion area than their ICAM-1(+/+) littermates: 4.08 +/- 0.70 mm(2) for -/- males vs. 5.87 +/- 0.66 mm(2) for +/+ males, and 3.95 /- 0.65 mm(2) for -/- females vs. 5.59 +/- 1.131 mm(2) for +/+ females, com bined P < 0.0001. An even greater reduction in lesion area was observed in P-selectin(-/-) mice: 3.06 +/- 1.04 mm(2) for -/- males vs. 5.09 +/- 1.22 m m(2) for +/+ males, and 2.85 +/- 1.26 mm(2) for -/- females compared with 5 .60 +/- 1.19 mm(2) for +/+ females, combined P < 0.001. The reduction in le sion area for the E-selectin null mice, although less than that seen for IC AM-1 or P-selectin, was still significant (4.54 +/- 2.14 mm(2) for -/- male s vs. 5.92 +/- 0.63 mm(2) for +/+ males, and 4.38 +/- 0.85 mm(2) for -/- fe males compared with 5.94 +/- 1.44 mm(2) for +/+ females, combined P < 0.01) . These results, coupled with the closely controlled genetics of this study , indicate that reductions in the expression of P-selectin, ICAM-1, or E-se lectin provide direct protection from atherosclerotic lesion formation in t his model.