P-Selectin or Intercellular Adhesion Molecule (Icam)-1 Deficiency Substantially Protects against Atherosclerosis in Apolipoprotein E–Deficient Mice

摘要

The expression of leukocyte and endothelial cell adhesion molecules (CAMs) is essential for the emigration of leukocytes during an inflammatory response. The importance of the inflammatory response in the development of atherosclerosis is indicated by the increased expression of adhesion molecules, proinflammatory cytokines, and growth factors in lesions and lesion-prone areas and by protection in mice deficient in various aspects of the inflammatory response. We have quantitated the effect of deficiency for intercellular 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 mm² for −/− males vs. 5.87 ± 0.66 mm² for +/+ males, and 3.95 ± 0.65 mm² for −/− females vs. 5.59 ± 1.131 mm² for +/+ females, combined P < 0.0001. An even greater reduction in lesion area was observed in P-selectin^−/− mice: 3.06 ± 1.04 mm² for −/− males vs. 5.09 ± 1.22 mm² for +/+ males, and 2.85 ± 1.26 mm² for −/− females compared with 5.60 ± 1.19 mm² for +/+ females, combined P < 0.001. The reduction in lesion area for the E-selectin null mice, although less than that seen for ICAM-1 or P-selectin, was still significant (4.54 ± 2.14 mm² for −/− males vs. 5.92 ± 0.63 mm² for +/+ males, and 4.38 ± 0.85 mm² for −/− females compared with 5.94 ± 1.44 mm² 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-selectin provide direct protection from atherosclerotic lesion formation in this model.