Cellular Adhesion Molecules and Selectins
Coronary artery disease and indeed all inflammatory vascular diseases are initiated and perpetuated by the interaction of immune cells with cells of the affected vessel wall. This is directed by a network of chemical messengers, which, in a state of vascular health, exist as balanced but opposing forces. The detection of vascular inflammation and monitoring of this activity have long been attempted in systemic vasculitis, and, more recently, in atherosclerosis. Markers of vascular inflammation used thus far have been of limited value; few provide both adequate sensitivity and specificity for any particular disease. New insights into the pathophysiology of vascular inflammation have identified other potential markers that may improve detection and monitoring of these conditions, including coronary thrombosis.
Immunomodulatory mediators of the inflammatory cascade have been identified and their roles are being defined. There are recent data that implicate various cytokines, proteases, adhesion molecules, and acute phase proteins as participants in the generation of vascular inflammation that may ultimately lead to thrombosis.
It was no more than 20 years ago, biologists believed that cell adhesion molecules were simply the glue of life, the stuff that served to hold cells and ligaments and everything else together. Since then, however, understanding of these molecules has gone through a paradigm shift. Today, the study of cell adhesion molecules has been transformed from a back-water of biology into one of the hottest fields around. Cell adhesion molecules are cell-surface glycoproteins, mediating cell-to-cell and cell-to-matrix adhesive interactions. Several of these proteins, including Inter Cellular Adhesion Molecule 1 (ICAM-1), are important in the regulation of inflammation and the immune response. Therefore cell adhesion molecules are at the centre of discussions of inflammation leading to coronary artery disease.
Cellular adhesion molecules (CAM) are essential in mediation of adhesion and transendothelial migration of leukocytes. In murine models, the absence of various CAM leads to reduced atherogenesis. Elevated ICAM-1 levels are predictive of cardiac events, independent of other risk factors, in men with and without coronary artery disease (CAD).
Although there is less evidence directly linking VCAM-1 levels to atherogenesis, it participates in key processes that implicate its role. VCAM-1 stimulates NAPDH oxidase, generating reactive oxygen species that alter endothelial cell structure, allowing for increased migration of leukocytes into the subendothelial space. VCAM-1 is expressed on endothelial cells in sites predisposed to plaque formation. In contrast to ICAM-1, which is expressed throughout atherosclerotic plaque, VCAM-1 is detected only in the rupture-prone areas. Although levels of VCAM-1 have not shown consistent association with atherosclerosis, an elevated VCAM-1 transcardiac gradient correlates with coronary endothelial dysfunction and progression of coronary atherosclerosis.
The selectins also mediate cell rolling and adhesion to the vessel wall. P-selectins mediate platelet-neutrophil interactions, one of several examples of the interconnection between inflammation and thrombosis. Although their role is less defined than those of ICAM-1 and VCAM-1, they have predictive value. Elevated P-selectin levels in women correlate with increased risk of future cardiovascular events, independent of traditional risk factors. Levels of P-selectin are also increased in patients with unstable coronary syndromes. The role of cellular adhesion molecules are only starting to yield clues about the origin and causes of coronary thrombosis.
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