Dokument: Vascular and cardiac effects of endothelium-specific bradykinin type-II receptor overexpression
| Titel: | Vascular and cardiac effects of endothelium-specific bradykinin type-II receptor overexpression | |||||||
| Weiterer Titel: | Vascular and cardiac effects of endothelium-specific bradykinin type-II receptor overexpression | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=67873 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20241209-110835-7 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Metry, Sara Refaat Azab [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. rer. nat. Kojda, Georg [Betreuer/Doktorvater] Prof. Dr. Läer, Stephanie [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | Cardiovascular diseases (CVDs) continue over many years now to be one of the leading causes of death worldwide. Exploring new pathways in pathogenesis of CVDs is necessary to guide the development of new therapeutic agents to decrease mortality and morbidity among patients with CVDs. Hypertension is a prominent risk factor for most CVDs. Bradykinin is an endogenous peptide exerting vasodilation on blood vessels through acting on bradykinin type-II receptors (B2R). This vasodilatory effect is thought to be mediated by nitric oxide (NO), prostacyclin and endothelium derived hyperpolarizing factor (EDHF). Evidence about role of B2R in blood pressure control came from bradykinin administration in vivo, B2R knockout (B2R-KO) models and studies on Angiotensin-Converting Enzyme Inhibitors (ACEI) where bradykinin levels increased following ACEI administration. However, results from B2R-KO models weren’t confirmatory and the B2R effects remains incompletely characterized. Therefore, B2R signalling, particularly in endothelium, was thoroughly investigated in this work to get new insights about vascular and cardiac effects of B2R pathway, in addition to the underlying mediators for these effects. To achieve this, an endothelium-specific human B2R overexpression mice model (B2tg) was used. Vascular reactivity studies were done with the aim of testing the responsiveness to bradykinin of aortic tissues to illustrate its vasodilatory effects and to understand the underlying mechanisms. Hemodynamic measurements [systolic blood pressure (sBP) and heart rate (HR)] of B2tg mice were measured by the tail-cuff method to investigate the systemic effects of B2R overexpression. A flow-mediated dilation (FMD) study was conducted to assess endothelial function in conduit blood vessels. Cardiac function under basal conditions were assessed by echocardiography. To gain new insights about novel proteins and biological processes related to B2R signalling, proteomic analysis was performed on aortic tissues. Bradykinin-induced vasodilation was shown ex vivo in aortic rings of B2tg mice confirming the overexpression of human B2R and validating the vasodilatory effect of bradykinin. This effect was dependent on the nitric oxide synthase enzyme (NOS). B2R overexpression affected some hemodynamics parameters demonstrated as a decrease in sBP and HR in B2tg mice. The decrease in sBP was not mediated by cyclooxygenase (COX) or NOS -derived products. FMD data did not show a significant effect of endothelial B2R overexpression. Likewise, under basal conditions endothelium-specific B2R has no particular effects on cardiac functions, but an increase in aortic valve mean velocity was observed that warrant further investigations. In B2tg mice, proteomic analysis revealed change in expression of proteins that are related to reactive oxygen species metabolic process, electron transport chain, cellular lipid metabolic process, cell migration, and angiogenesis. Furthermore, several proteins e.g. CD44, hyaluronidase 1 and uncoupling protein 1 that are most likely related to endothelial B2R signalling, were newly reported. These findings increase the current knowledge on the role of B2R signalling in blood pressure regulation and provide new aspects about vascular and cardiac effects of the endothelial B2R overexpression under basal conditions. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät » Institute » Institut für Pharmakologie und Klinische Pharmakologie | |||||||
| Dokument erstellt am: | 09.12.2024 | |||||||
| Dateien geändert am: | 09.12.2024 | |||||||
| Promotionsantrag am: | 04.07.2024 | |||||||
| Datum der Promotion: | 07.11.2024 |
