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

Abstract

Abstract-Intercellular adhesion molecule (ICAM)-1, a major adhesion molecule, plays a critical role in the homing of leukocytes to sites of atherosclerotic lesions. However, very little is known on the role of ICAM-1 in initiating and perpetuating vascular lesions in ApoE Ϫ/Ϫ mice fed a chow or a fat diet. This study has investigated the mean aortic lesions in mice (C57BL6 background) with a single-knockout (ApoE Ϫ/Ϫ ) or double-knockout (DKO; ApoE Ϫ/Ϫ , ICAM-1 Ϫ/Ϫ ) fed a chow or a fat diet over a period of 3, 6, 15, and 20 weeks. A 3-fold reduction in lesion size was observed at all time points in DKO mice fed a chow diet. However, in DKO mice fed a fat diet, a marked reduction in the aortic lesion was observed at 3 and 15 weeks, which did not reach a significant level at 6 and 20 weeks. This study shows in essence that DKO mice are protected from developing significant lesions for up to 6 weeks when fed a chow diet and from 3 to 6 weeks when fed a fat diet. After 6 weeks, the lesion size of the DKO mice follows that of the single-knockout mice when fed a chow diet and gets to the same level in mice fed a fat diet. Plasma cholesterol levels were not altered as a result of ICAM-1 deficiency. These studies show that ICAM-1 is implicated in the formation and progression of atherosclerotic lesions.

Laser capture microdissection analysis of gene expression in macrophages from atherosclerotic lesions of apolipoprotein E-deficient mice

“…For example, the proatherogenic effect of VCAM-1 has been demonstrated by the decreased lesion size in low density lipoprotein receptor-deficient mice containing a targeted deletion of the VCAM-1 gene (32). Similarly, ICAM-1 deficiency reduced atherosclerosis in both diet-induced (33) and apoE-deficient animals (34). The importance of MCP-1 has been demonstrated by a decrease in atherosclerosis in mice that lack either MCP-1 (35) or its receptor, CCR2 (25).…”

ICAM-1: Contribution to Vascular Inflammation and Early Atherosclerosis

“…The involvement of ICAM-1 in atherosclerosis has been demonstrated in apoE -/-mice deficient in ICAM-1, which had reduced lesion size (Nageh, Sandberg et al 1997). Time course analysis revealed that ICAM-1 is not only involved in the initial plaque formation but also in subsequent progression in mice (Bourdillon, Poston et al 2000;Kitagawa, Matsumoto et al 2002). These data were supported by results obtained in apoE -/-mice treated with anti-ICAM-1 neutralising antibodies (Patel, Thiagarajan et al 1998).…”

Anti-Inflammatory Properties of HDL

“…85 It has been proposed that the atheroprotective effects of antibodies directed against the CD40 ligand are achieved by an inhibition of endothelial cell VCAM-1 expression. 86 The effects of reduced ICAM-1 expression are inconsistent, with both positive 87 and negative 88 results reported. Various selectins and members of the immunoglobulin superfamily also exist in a soluble plasma form in concentrations that have been shown in some studies to correlate with the presence of other cardiovascular risk factors.…”

“…85 It has been proposed that the atheroprotective effects of antibodies directed against the CD40 ligand are achieved by an inhibition of endothelial cell VCAM-1 expression. 86 The effects of reduced ICAM-1 expression are inconsistent, with both positive 87 …”