Martin M N Schmitt1, Line Fraemohs2, Tilman M Hackeng3, Christian Weber4, Rory R Koenen5. 1. 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. 2. Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany. 3. Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands. 4. 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. 5. 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.
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.
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.
Authors: Zhen Zhao; Tanja Vajen; Ela Karshovska; Annemiek Dickhout; Martin M Schmitt; Remco T A Megens; Philipp von Hundelshausen; Thomas A Koeppel; Tilman M Hackeng; Christian Weber; Rory R Koenen Journal: J Cell Mol Med Date: 2017-02-17 Impact factor: 5.310
Authors: Mario Amatruda; Candice Chapouly; Viola Woo; Farinaz Safavi; Joy Zhang; David Dai; Anthony Therattil; Chang Moon; Jorge Villavicencio; Alexandra Gordon; Charles Parkos; Sam Horng Journal: Brain Commun Date: 2022-02-18