Adhesion molecules in atherosclerosis – ICAM1

Direct cell-cell interactions are maintained and regulated by cell adhesion molecules. The expression of adhesion molecules directs inflammatory responses (Walpola et al., 1994). Early adhesion molecules include P and E selectins which slow down leukocyte movements along the endothelium wall so adhesion molecules such as VCAM-1 and ICAM-1 can attach to the ligand on leukocytes (Leeuwenberg et al., 1992, Libby, 2006). Soluble forms of these adhesion molecules are also found in the supernatant of cytokine activated cultured endothelial cells (Pigott et al., 1992).

In atherosclerosis, adhesion molecules are upregulated by cytokines and shear stress to facilitate the attachment of leukocytes to the activated endothelium and permit their transmigration into the intima where they accumulate and form foam cells at sites predisposed to atherosclerosis (Frank and Lisanti, 2008).

Intercellular adhesion molecule 1 (ICAM-1) is a member of the immunoglobulin superfamily along with ICAM-2/3, vascular cell adhesion molecule 1 (VCAM-1) and platelet endothelial cell adhesion molecule 1 (PECAM-1). They are glycoprotein receptors found on the endothelial membrane and each posses a different number of extracellular Ig domains (Blankenberg et al., 2003).

ICAM-1 expression is distributed around the cell under normal shear stress with an abundance in the junctional regions. In normal healthy coronary arteries ICAM-1 is expressed. However, it has also been identified in all plaque types in both ECs and macrophages (Davies et al., 2005). In inflamed regions ICAM-1 expression on ECs is controlled by cytokines such as VEGF and TNF-alpha and synthesized via RhoA activation and the NF-ĸβ pathway (Thompson et al., 2002, Kim et al., 2001). In murine model studies, ICAM-1 deficiency alone did not prevent lesion formation and Cybulsky et al., concluded VCAM-1 as a more significant role in atheroma initiation (Cybulsky et al., 2001). Walpola reported that an increase in SS upregulates ICAM-1 expression in rabbit carotid arteries while a reduction in SS is proportionate to ICAM-1 expression (Walpola et al., 1994).

In human studies, circulating levels of ICAM-1 have been measured in coronary and carotid artery disease patients. Both produce higher levels compared to healthy controls but levels do not vary between these two groups (Hwang et al., 1997). An upregulation of ICAM-1 in circulation has also been linked to myocardial infarctions and future coronary events (Luc et al., 2003). This may suggest a promising molecular marker for atherosclerosis. However, systemic reduction of monocyte adhesion could be potentially dangerous as a therapeutic strategy against atherosclerosis. Nonetheless, mice models with significant adhesion molecule reductions look promising (Nagel et al., 1997).