Adhesion Molecules and Oxidized Low-density Lipoprotein - Adhesion Molecules - page 394

establish more specii c and ef ective treatment modalities for atherosclerosis and
cutaneous xanthomas.
INTRODUCTION
h e common histological feature of atherosclerosis and cutaneous xanthomas is
the ini ltration of the lesions by macrophage-derived lipid-laden foam cells. h 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 i 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 lipid-
containing and i brous plaques. P-selectin is detected in atherosclerotic plaques,
but not in i brous plaques. ICAM-1 expression is also increased in all subtypes
of atherosclerotic lesions except for i 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 specii 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. h e mechanisms of adhesion molecule expression
vary depending on the process of LDL oxidation and the organ specii city of the
endothelial cells. h is chapter summarizes recent studies of the mechanisms of
endothelial adhesion molecule expression induced by Ox-LDL.