Atherogenic mononuclear cell recruitment is facilitated by oxidized lipoprotein-induced endothelial junctional adhesion molecule-A redistribution

Abstract

Background: Junctional adhesion molecule (JAM-) A is a transmembrane protein expressed in many cell types and maintains junctional integrity in endothelial cells. Upon inflammatory stimulation, JAM-A relocates to the apical surface and might thereby facilitate the recruitment of leukocytes.

Objective: Although inflammatory JAM-A redistribution is an established process, further effort is required to understand its exact role in the transmigration of mononuclear cells, particularly under atherogenic conditions.

Methods: By the use of RNA interference and genetic deletion, the role of JAM-A in the transmigration of T cells and monocytes through aortic endothelial cells was investigated. JAM-A-localization and subsequent mononuclear cell rolling, adhesion and transmigration were explored during endothelial inflammation, induced by oxidized LDL or cytokines.

Results: RNA interference or genetic deletion of JAM-A in aortic endothelial cells resulted in a decreased transmigration of mononuclear cells. Treatment of the endothelial cells with oxLDL resulted in an increase of both permeability and apical JAM-A presentation, as shown by bead adhesion and confocal microscopy experiments. Redistribution of JAM-A resulted in an increased leukocyte adhesion and transmigration, which could be inhibited with antibodies against JAM-A or by lovastatin-treatment, but not with the peroxisome proliferator activated receptor gamma-agonist pioglitazone.

Conclusions: This study demonstrates that redistribution of JAM-A in endothelial cells after stimulation with pro-atherogenic oxidized lipoproteins results in increased transmigration of mononuclear cells. This inflammatory dispersal of JAM-A could be counteracted with statins, revealing a novel aspect of their mechanism of action.

Keywords: Atherosclerosis; Endothelial cells; F11R; JAM-1; Junctional adhesion molecule; Statin; Transmigration.