Atherogenic mononuclear cell recruitment is facilitated by oxidized lipoprotein-induced endothelial junctional adhesion molecule-A redistribution.
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.
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany; Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
Martin M N
MM
Schmitt
Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany.
Line
L
Fraemohs
Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
Tilman M
TM
Hackeng
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands; German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
Christian
C
Weber
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands. Electronic address: r.koenen@maastrichtuniversity.nl.
Rory R
RR
Koenen
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D036904:Leukocyte Rolling; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008148:Lovastatin / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability; D000077205:Pioglitazone; D021381:Protein Transport; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects; D014162:Transfection
D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D015815:Cell Adhesion Molecules; C407243:F11R protein, human; C498686:F11r protein, mouse; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D011956:Receptors, Cell Surface; D045162:Thiazolidinediones; C099252:oxidized low density lipoprotein; D008148:Lovastatin; D000077205:Pioglitazone
Atherosclerosis; Endothelial cells; F11R; JAM-1; Junctional adhesion molecule; Statin; Transmigration