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

Abstract

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.

Increased Expression of Adhesion Molecules in Uremic Atherosclerosis in Apolipoprotein-E–Deficient Mice

“…This is mainly due to selectin ligation, whereas the subsequent firm adhesion depends on interactions between Ig-like molecules (ICAM-1, VCAM-1) on the endothelium and integrins on the leukocyte surface. Knockout mice that lack E-selectin, ICAM-1, or VCAM-1 and mice treated with antibodies against adhesion molecules display reduced atherosclerosis (12)(13)(14)(25)(26)(27).…”

“…It is well established that inhibition of the expression of adhesion molecules retards development of classical atherosclerosis in animal models, probably by slowing down the recruitment of inflammatory cells from the blood (12)(13)(14). Patients with CRF display increased plasma concentrations of soluble portions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) (15).…”

ICAM-1 Deficiency Reduces Atherosclerotic Lesions in Double-Knockout Mice (ApoE − /− /ICAM-1 − /− ) Fed a Fat or a Chow Diet

“…While this manuscript was being revised, the work by Collins et al 46 has been published. The authors report atherosclerosis in ApoE knockout animals also having a deficiency in ICAM-1 or P-selectin or E-selectin.…”

VCAM-1 is critical in atherosclerosis

“…Working with a C57BL/6 mouse model fed a high-cholesterol diet containing cholate, Nageh et al (12) showed that aortic lesion size is significantly reduced in ICAM-1 or P-selectin null mice or in mice with a hypomorphic mutation in the gene encoding the common CD18 subunit of β 2 integrins. In the more realistic apoE knockout model of atherosclerosis, in which mice have cholesterol levels between 500 and 2,000 mg/dl, depending on the diet offered, animals lacking P-selectin or ICAM-1 show significantly smaller aortic lesions (13,14). In a milder model of atherosclerosis, the LDL receptor knockout mouse, absence of P-selectin showed only a modest benefit in male mice and no benefit in female mice (15).…”