Abstract 19930: Inflammatory Cytokine Oncostatin M Induces Endothelial Activation in vitro and in APOE*3Leiden.CETP Mice
Introduction: Endothelial activation is involved in all stages of atherosclerosis development. Upon endothelial activation, the endothelial barrier becomes more permeable and starts recruiting immune cells. This process is often initiated by cytokines. We hypothesized that the cytokine Oncostatin M (OSM), which is synthesized by activated T-cells and monocytes and is relatively unknown in the field of atherosclerosis, induces endothelial activation.
Methods: Human umbilical vein endothelial cells (HUVECs) were cultured in the presence of OSM and OSM was administered to APOE*3Leiden.CETP mice. Features of endothelial cell activation were assessed by qPCR, flow cytometry, Luminex, and immunohistochemistry. Involvement of the JAK/STAT signaling cascade was investigated by western blot.
Results: In vitro, OSM increased intercellular adhesion molecule (ICAM)-1 (296±16%, n=3), interleukin (IL)-6 (742±127, n=4) and monocyte chemoattractant protein (MCP)-1 (307±48, n=4) mRNA expression. These findings were supported by enhanced protein release of IL-6 (651±228, n=5) and MCP-1 (261±93, n=5), and enhanced membrane expression of ICAM-1 (169±19%, n=3). Specific silencing of the OSM receptor expression by siRNA in combination with OSM reduced IL-6 (18±3%, n=3) and MCP-1 (43±1%, n=3) release. These findings were confirmed in vivo where OSM treatment enhanced aortic IL-6 mRNA expression (514±87, n=8), and increased plasma levels of E-selectin (193±23%, n=8) and MCP-1 (163±27%, n=8) in mice. Furthermore, ICAM-1 protein expression (151±20%, n=8) and monocyte adhesion (180±27%, n=8) were increased in the aortic root. Increased phosphorylation of STAT-1 (163-fold±57, n=2) and STAT-3 (29-fold±1, n=2) in HUVECs, indicates that OSM signals through the JAK/STAT pathway.
Conclusion: Taken together, these results suggest that OSM induces endothelial activation both in vitro and in vivo through activation of the JAK/STAT cascade. Since endothelial activation is crucial in atherosclerosis development, OSM may play a role in the initiation and progression of atherosclerotic lesion formation. Therefore, targeting of this cytokine may provide a novel approach in the treatment of atherosclerosis.
Author Disclosures: D. van Keulen: Employment; Significant; Quorics B.V.. M.G. Pouwer: None. G. Pasterkamp: None. A.J. van Gool: None. M.D. Sollewijn Gelpke: None. H.M. Princen: None. D. Tempel: Employment; Significant; Quorics B.V..
- © 2017 by American Heart Association, Inc.