Dokument: Rolle zyklischer Nukleotide in der Regulation der Expression von Angiotensin II-Typ-2-Rezeptoren
| Titel: | Rolle zyklischer Nukleotide in der Regulation der Expression von Angiotensin II-Typ-2-Rezeptoren | |||||||
| Weiterer Titel: | Role of Cyclic Nucleotides in the Regulation of the Expression of Angiotensin II- Type 2 Receptors | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=34363 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20150601-104420-1 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Dr Agouri, Sawsan [Autor] | |||||||
| Dateien: |
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| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | There are some vascular signalling interactions between the vascular endothelial NO system and the renin-angiotensin aldosterone system (RAAS), for example activation of AT2 receptors lead to the generation of cGMP. The aim of these studies was to investigate whether endothelial nitric oxide (NO) has any influence on the expression of angiotensin (Ang) type 1 (AT1) and type 2 (AT2) receptors. The interaction between the RAAS and the NO/cGMP system was identified. NO donors increased the expression of the angiotensin II (Ang II) type 2 receptorss (AT2). In striking contrast, the expression of the AT1 receptor did not change. The interaction was confirmed by investigations in primary cell culture. The experiments obtained in vitro with different endothelial cells and in vivo with transgenic animals, show that the NO/cGMP and the MAPK signal transduction pathways are likely involved in the underlying mechanism. Primary cultures of porcine aortic endothelial cells (PAEC) and human umbilical vein endothelial cells (HUVEC) and the cell line brain mouse endothelial cells (bEND.3) were used. The incubation of these cells with different NO donors such as SNAP (S-nitroso-N-acetyl-D-L-pencilliamin), and/or DEA/NO (DiethylamineNONate) and DETA/NO (Diethylenetriamine /nitric oxide) and significantly increased AT2 protein expression as determined by western blot. Likewise, AT2 mRNA expression was determined by RT PCR in bEND.3 cells. AT2 mRNA expression was increased after DEA/NO incubation. AT2 mRNA stability remained unchanged suggesting a transcriptional mechanism. Studies on time and concentration dependently AT2 following NO stimulation revealed that long-term exposure of bEND3 cells with the 24 hours NO releasing compound DETA/NO resulted in continuous upregulation of AT2 protein levels which plateaued at 12 hours. Furthermore, co-incubation of PAEC with the soluble guanylate cyclase (sGC) inhibitor ODQ (oxidiazolol quinoxalin) or protein kinase G (PKG) inhibitor (RP-pCPT cGMP) abolished NO- induced AT2 upregulation. Treatment of PAEC with the PDE-V inhibitor sildenafil, the protein kinase G (PKG) activators, 8-pCPT-cGMP (8 para chlorophenylthioguanosin – cGMP) and 8-Br-cGMP (8- Bromo-guanosine 3, 5 cyclic monophosphate) resulted in significantly increased AT2 protein expression.
In addition, treatment of PAEC with either DEA/NO or 8-pCPT-cGMP increased phosphorylation of p38 MAPK, a kinase known to be involved in NO/cGMP signalling. Accordingly, co-incubation of PAEC with DEA/NO and the p38 MAPK inhibitor (SB203580) abolished NO induced AT2 upregulation and phosphorylation of p38 MAPK. These results suggest that NO induced vascular AT2 upregulation is mediated by activation of the NO/cGMP pathway including stimulation of sGC and PKG and subsequent induction of p38 MAPK phosphorylation. In addition, a significant increase in AT2 protein expression was detected in a transgenic mouse line overexpressing eNOS in an endothelial-dependent manner and of a magnitude that strongly reduced blood pressure. Furthermore, this increase was not only completely abolished by the NO synthase inhibitor L- NAME but strongly reduced so that there was no difference to L-NAME treated transgene negative littermates anymore. The upregulation of AT2 receptors by NO is a newly discovered interaction between the RAAS and the NO system. The importance of this new pathway for the development of endothelial dysfunction and/or the pathophysiology of cardiovascular disease such as coronary artery disease, hypertension, heart failure, or stroke has to be clarified. On the other hand, NO-induced increase of AT2 may be invoved in the development of known side effect of cardiovascular drugs like AT1 blockers, i.e. angioedema. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät | |||||||
| Dokument erstellt am: | 01.06.2015 | |||||||
| Dateien geändert am: | 01.06.2015 | |||||||
| Promotionsantrag am: | 01.09.2014 | |||||||
| Datum der Promotion: | 03.11.2014 |
