Abstract 322: Azathioprine Reduces Endothelial Cell Activation via Inhibition of GTPase Rac1
| Autor: | Goran Marinkovic, Mark Hoogenboezem, Jaap van Buul, Carlie J de Vries, Vivian de Waard |
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| Rok vydání: | 2013 |
| Předmět: | |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 33 |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvb.33.suppl_1.a322 |
| Popis: | Objective Azathioprine (AZA) and its active metabolite 6-mercaptopurine (6-MP) are well established immunosuppressive drugs. Common understanding of its immunosuppressive properties is largely limited to immune cells. However, 6-MP also has a potential to effectively modulate the inflammatory phenotype of endothelial cells. Activation of endothelium is a fundamental feature in chronic inflammatory diseases. We studied the mechanism underlying the protective role of the immunosuppressive drug 6-MP in endothelial cell activation. Methods and Results Since it is known that Aza affects small GTPase Rac1 in T-cells, we focussed on Rac1-mediated processes in cultured endothelial cells in the presence or absence of 6-MP. Indeed, upon treatment with 6-MP, we observed a decrease of GTP-bound Rac1, confirming that there is less active Rac1. Reduced activity of Rac1 influences the downstream signaling cascade, resulting in decreased phosphorylation of c-Jun terminal N-Kinase (JNK), c-Jun and thus, reduced transcription of pro-inflammatory genes. On mRNA level, in the presence of 6-MP we confirmed that endothelial cells express less proinflammatory chemokine CCL5 (Rantes), Interleukin-12 and adhesion molecule VCAM1; genes downstream of the Rac1-mediated JNK signalling pathway. In addition, monocyte adhesion to activated endothelial cells is strongly inhibited upon 6-MP treatment, Indeed, reduced cytoskeletal rearrangement is observed in the form of actin protrusions that capture leukocytes, which is a process that relies on Rac1 activation. Specifically, a 47% reduction in number of transmigratory cups is observed, resulting in a reduction of adherent Anti-ICAM-1 Ab-coated beads (monocytes substitute). Conclusion These data underscore the anti-inflammatory effect of 6-MP on endothelial cells, modulating the activation response of endothelial cells in a Rac1-dependent fashion and providing us with a mechanistic insight for the development of novel therapeutic targets against chronic inflammatory diseases. |
| Databáze: | OpenAIRE |
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