Oxidized low density lipoprotein-induced LFA-1-dependent adhesion and transendothelial migration of monocytes via the protein kinase C pathway

Abstract

Inflammatory and immune responses are highly relevant processes in the pathogenesis of atherosclerosis, as illustrated by the central event of monocyte accumulation in atherosclerotic plaques. Integrin LFA-1-mediated adhesion of circulating monocytes to the endothelium is a prerequisite for recruitment of monocytes to these areas. Integrin-mediated adhesion is tightly regulated and integrins are only functional in response to particular monocyte activation stimuli. We investigated the role of oxidized low-density lipoprotein (LDL) in adhesion of resting monocytes prepared by elutriation from endothelium. Our results showed that: (1) oxidized LDL (and MCP-1) induced both LFA-1-mediated adhesion of monocytes to endothelial cells and transendothelial migration of monocytes; (2) oxidized LDL functionally transformed monocyte LFA-1 to an activated form; (3) oxidized LDL induced F-actin polymerization and cytoskeletal rearrangement within seconds; and (4) the LDL-associated antioxidant, α-tocopherol, but not β-tocopherol, inhibited both F-actin polymerization and LFA-1-mediated adhesion of monocytes, which paralleled the effect of protein kinase C (PKC) inhibitors. Our results indicate that oxidized LDL plays a pivotal role in triggering LFA-1 activation and LFA-1-mediated adhesion and transmigration of monocytes to sites of atherosclerotic plaques, via the PKC pathway.