JAM-A: Junctional Adhesion Molecule-A or Janus Acting Mediator in atherosclerosis

Presently, atherosclerosis constitutes one of the leading causes for patients suffering morbidity and death around the world with no expected changes in frequency the next decades. A lot of efforts to find powerful therapeutic targets had been taken already, but the range of useful drugs is still comparably limited regarding the broad causalities of this multifaceted disease. Still plenty of crucial cellular and molecular mechanisms facilitating atherosclerosis are not understood completely. As atherosclerosis is a chronic inflammation of the vessel wall, leukocyte – endothelial cell interaction is one of the determining factors for atherosclerotic lesion formation. Thus, investigating mechanisms underlying leukocyte recruitment is important for development of novel therapeutic strategies as they still are not explored to a satisfying degree. One of the involved adhesion molecules, at which attention had be drawn to already years ago, is JAM-A. Over the years a rag rug of roles for JAM-A expressed by differing cell types in different inflammatory setups was generated. For example the role of JAM-A in injury models of liver, carotid artery and heart had been investigated, sometimes with contrary results, but a conclusive study directly comparing the role of JAM-A from differing cellular origin on atherogenesis is still missing. With this study, we aimed to unravel the influence of the adhesion molecule JAM-A expressed from different cell types on atherosclerotic lesion formation and progression. Meanwhile, identified new concepts of leukocyte extravasation and were able to verify established ones. In detail, we found that:1. JAM-A from differing cellular origin exerts diverse effects on atherogenesis2. Whereas somatic deficiency has no effect, endothelial JAM-A deficiency reduces plaque formation via decreasing leukocyte recruitment3. Leukocytes deficient for JAM-A lack active transmigratory capacity and damage the vessel wall, thus enhancing plaque formation4. Endothelial JAM-A is more abundant on the cell surface under hyperlipidemic and altered shear stress conditions5. Normal flow conditions exert atheroprotective function by reducing JAM-A expression via increased miR-145 levels6. Lovastatin completely abolishes oxidized LDL-mediated JAM-A re-localization and increase in leukocyte infiltration