Effects of different serotonin receptor subtype antagonists on the development of cardiac allograft vasculopathy in murine aortic allografts
| Autor: | Jörg H W Distler, A. Gocht, Stephan M. Ensminger, Martina Ramsperger-Gleixner, Bernd M. Spriewald, Christian Heim, Michael Weyand |
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| Rok vydání: | 2018 |
| Předmět: |
Graft Rejection
Male 0301 basic medicine Neointima Serotonin Indoles Receptor expression Immunology Sarpogrelate SB-204741 030204 cardiovascular system & hematology Pharmacology Terguride Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Animals Humans Transplantation Homologous Urea Immunology and Allergy Medicine Platelet activation Lisuride Aorta 5-HT receptor Cell Proliferation Transplantation business.industry Transendothelial and Transepithelial Migration Succinates Mice Inbred C57BL 030104 developmental biology chemistry Models Animal Mice Inbred CBA Serotonin 5-HT2 Receptor Antagonists cardiovascular system Heart Transplantation Female Serotonin Antagonists business medicine.drug |
| Zdroj: | Transplant Immunology. 49:43-53 |
| ISSN: | 0966-3274 |
| DOI: | 10.1016/j.trim.2018.04.002 |
| Popis: | Background Cardiac allograft vasculopathy (CAV) is the main obstacle for long-term survival after heart transplantation. Alloimmune mediated chronic vascular rejection results in several mechanisms like platelet activation, immigration of inflammatory cells through the endothelial layer and proliferation and migration of smooth muscle cells (SMCs). Serotonin (5-HT) promotes these processes via activation of 5-HT2 receptors. We hypothesized that inhibiting 5-HT2 receptors ameliorates the development of CAV. Methods CBA/JRj mice recieved aortic grafts from C57BL/6 mice. After transplantation until recovery of organs, recipients were treated with serotonin receptor antagonists: sarpogrelate (5-HT2A), SB 204741 (5-HT2B) or terguride (5-HT2A+B). Mice were sacrificed after 14 days for qRT-PCR analysis or after 30 days for histological evaluation. Serum serotonin ELISA was done at both time points. Results Elevated serum serotonin levels were significantly reduced after 5-HT2A antagonist treatment as was 5-HT2A receptor expression. This went along with reduced inflammation characterized by significantly fewer infiltrating macrophages and pro-inflammatory intragraft cytokines and with reduced tissue remodeling evident as significantly less neointima formation. Conclusion Inhibition of the 5HT/5-HT2A receptor axis leads to significantly reduced neointima proliferation after aortic transplantation associated with reduced transendothelial migration of macrophages and decreased expression of inflammatory cytokines. These findings have translational implications as inhibitors of 5HT2A like sarpogrelate are already approved for clinical use. |
| Databáze: | OpenAIRE |
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