Deficiency of Inflammatory Cell Adhesion Molecules Protects Against Atherosclerosis in Mice

Abstract

Leukocyte and endothelial cell adhesion molecules (CAMs) are essential for emigration of leukocytes, with the selectins mediating the initial step of leukocyte "rolling" and the beta 2-(CD18) integrins and intercellular adhesion molecule-1 (ICAM-1) being important for firm adhesion and emigration. On the basis of evidence for an inflammatory component in the pathogenesis of atherosclerosis, including increased expression of CAMs, cytokines, and growth factors, we tested the hypothesis that decreased expression of inflammatory CAMs would reduce susceptibility to atherosclerosis. Using C57BL/6 mice fed a high-fat diet, we observed a 50% to 75% reduction in atherosclerotic fatty streaks in mice 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 evidence of increased expression of CAMs in atherosclerotic lesions, which does not prove a cause-and-effect relationship, these data indicate directly that the level of expression of CAMs can determine the susceptibility to the formation of atherosclerotic fatty streaks. The results suggest that genetic variation at these loci could influence susceptibility to atherosclerosis and that pharmacological reduction of the expression or function of these CAMs might protect against atherosclerosis.

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

“…Deficiency of ICAM-1 expression in C57BL6 fat-fed animals showed a 75% protection against atherosclerosis when compared with wild-type animals. 23 However, one should note that ApoE-deficient animals fed a fat diet probably show lesions that are closer, compared with C57BL6, to those seen in human. Our data support a role for ICAM-1 at all stages of atherosclerosis in chow-fed animals.…”

“…Morphometric analyses of intima lesion area over media area were carried out on the whole circumference of the proximal aortic arch, with the use of a previously described quantification method. 14,23,30 The number of sections used per animal was at least 5 per animal and per time point. Measurements were performed on ORO-stained slides for the different weeks of feeding (5 mice per group).…”

“…22 Finally, ICAM-1 knockout in a C57BL6 fat-fed model greatly reduced the size of vascular lesions. 23 This study has investigated the size of aortic arch lesions in mice deficient in ApoE Ϫ/Ϫ , ICAM-1 Ϫ/Ϫ (double-knockout, DKO) and compared them with ApoE Ϫ/Ϫ -deficient (single-knockout, SKO) mice.…”

VCAM-1 is critical in atherosclerosis

“…Although VCAM-1 knockout mice were unavailable, other adhesion molecule-deficient mice have been tested successfully in various models of 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).…”

Soluble integrin adhesion receptors and atherosclerosis: much heat and a little light?

“…[7][8][9] Furthermore, mice deficient in VCAM-1 are protected against the development of atherosclerosis, 10 whereas the data regarding ICAM-1 knockout mice are conflicting. [10][11][12][13] Cell-bound adhesion receptors are relatively inaccessible in vivo. Fortuitously, soluble forms of VCAM-1 and ICAM-1 are found within the circulation.…”