Abstract
AimsEndothelial activation is involved in many chronic inflammatory diseases, such as atherosclerosis, and is often initiated by cytokines. Oncostatin M (OSM) is a relatively unknown cytokine that has been suggested to play a role in both endothelial activation and atherosclerosis. We comprehensively investigated the effect of OSM on endothelial cell activation from different vascular beds and in APOE*3Leiden.CETP mice.Methods and resultsHuman umbilical vein endothelial cells, human aortic endothelial cells and human microvascular endothelial cells cultured in the presence of OSM express elevated MCP-1, IL-6 and ICAM-1 mRNA levels. Human umbilical vein endothelial cells and human aortic endothelial cells additionally expressed increased VCAM-1 and E-selectin mRNA levels. Moreover, ICAM-1 membrane expression is increased as well as MCP-1, IL-6 and E-selectin protein release. A marked increase was observed in STAT1 and STAT3 phosphorylation indicating that the JAK/STAT pathway is involved in OSM signaling. OSM signals through the LIF receptor alfa (LIFR) and the OSM receptor (OSMR). siRNA knockdown of the LIFR and the OSMR revealed that simultaneous knockdown is necessary to significantly reduce MCP-1 and IL-6 secretion, VCAM-1 and E-selectin shedding and STAT1 and STAT3 phosphorylation after OSM stimulation. Moreover, OSM administration to APOE*3Leiden.CETP mice enhances plasma E-selectin levels and increases ICAM-1 expression and monocyte adhesion in the aortic root area. Furthermore, Il-6 mRNA expression was elevated in the aorta of OSM treated mice.ConclusionOSM induces endothelial activation in vitro in endothelial cells from different vascular beds through activation of the JAK/STAT cascade and in vivo in APOE*3Leiden.CETP mice. Since endothelial activation is an initial step in atherosclerosis development, OSM may play a role in the initiation of atherosclerotic lesion formation.
Highlights
The endothelium is involved in many processes including maintenance of the endothelial barrier function, prevention of spontaneous blood clot formation, inflammatory cell recruitment upon injury and regulation of the vascular tone[1,2,3]
Since endothelial activation is an initial step in atherosclerosis development, oncostatin M (OSM) may play a role in the initiation of atherosclerotic lesion formation
OSM is upregulated in multiple chronic inflammatory diseases including periodontitis, rheumatoid arthritis and inflammatory bowel diseases and is known to induce angiogenesis and smooth muscle cell proliferation and migration, both processes that are involved in atherosclerosis development[7,8,9,10,11,12,13,14,15,16]
Summary
The endothelium is involved in many processes including maintenance of the endothelial barrier function, prevention of spontaneous blood clot formation, inflammatory cell recruitment upon injury and regulation of the vascular tone[1,2,3]. The process of endothelial activation can occur both, locally on well-known predilection sites and systemically, and is often triggered by traditional cardiovascular risk factors such as hypercholesterolemia, hypertension, smoking or diabetes and is initiated by inflammatory cytokines. One such a cytokine, which was first discovered in the cancer field, is oncostatin M (OSM). OSM is upregulated in multiple chronic inflammatory diseases including periodontitis, rheumatoid arthritis and inflammatory bowel diseases and is known to induce angiogenesis and smooth muscle cell proliferation and migration, both processes that are involved in atherosclerosis development[7,8,9,10,11,12,13,14,15,16]. OSM is found in human carotid atherosclerotic plaques and in the intima and media of atherosclerotic mice[16]
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