ABSTRACT
Th e common histological feature of atherosclerosis and cutaneous xanthomas is the infi ltration of the lesions by macrophage-derived lipid-laden foam cells. Th e migration of circulating monocytes into the lesions leads to the progression of the two diseases. Adhesion molecules on vascular endothelial cells play a critical role in leukocyte rolling, adhesion, and transmigration. E-selectin and P-selectin facilitate the rolling of leukocytes prior to fi rm adhesion. Monocyte adhesion to endothelial cells is mediated by the immunoglobulin superfamily, including intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). An enlargement of atherosclerotic lesions is inhibited by either the inhibition or hypomorphic mutation of any of these four adhesion molecules. In human atherosclerosis, E-selectin is expressed on endothelial cells in lipidcontaining and fi brous plaques. P-selectin is detected in atherosclerotic plaques, but not in fi brous plaques. ICAM-1 expression is also increased in all subtypes of atherosclerotic lesions except for fi brous plaques. VCAM-1 is more prevalent in the intima of atherosclerotic plaques than in the non-atherosclerotic segments of coronary arteries.However, the E-selectin expression is more specifi c for the atherosclerotic intima than either ICAM-1 or VCAM-1 expression because E-selectin is not detected in any control segments. E-selectin-positive endothelial cells are more prevalent in xanthoma lesions than in normal skin. In contrast, the ICAM-1 expression is less prevalent in xanthoma lesions than in normal skin. Almost all ICAM-1-positive endothelial cells in xanthomas co-express E-selectin, but there are also many endothelial cells in these lesions that only express E-selectin. Very few, if any, endothelial cells express VCAM-1 in either xanthoma lesions or normal skin. Evidence from in vitro studies indicates that oxidation of low-density lipoprotein (LDL; Fig. 1; see also Key Facts about Low-density Lipoprotein) induces adhesion molecule expression on endothelial cells and enhances monocyte binding to the endothelial cell membrane (Fig. 2). A reasonable inference drawn from this evidence is that oxidized low-density lipoprotein (Ox-LDL) binds to endothelial receptors (including scavenger receptors) and activates an intracellular signal transduction pathway that induces the expression of adhesion molecules on the surface of endothelial cells (Fig. 3). Circulating monocytes adhere to the endothelial cells via the Ox-LDL-induced adhesion molecules and subsequently transmigrate into the lesions. Th e mechanisms of adhesion molecule expression vary depending on the process of LDL oxidation and the organ specifi city of the endothelial cells. Th is chapter summarizes recent studies of the mechanisms of endothelial adhesion molecule expression induced by Ox-LDL.
