Dokument: Die Rolle der erythrozytären und endothelialen NOS3 in der Anämie und deren kardioprotektive Effekte nach myokardialer Ischämie/Reperfusionsschaden
| Titel: | Die Rolle der erythrozytären und endothelialen NOS3 in der Anämie und deren kardioprotektive Effekte nach myokardialer Ischämie/Reperfusionsschaden | |||||||
| Weiterer Titel: | The role of erythrocytic and endothelial NOS3 in anemia and their cardioprotective effects after myocardial ischemia/reperfusion injury | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=67989 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20250130-130044-8 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Nolde, Sophie [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof.Dr. Kelm, Malte [Gutachter] Prof. Dr. Germing, Ulrich [Gutachter] | |||||||
| Stichwörter: | eNOS, Anämie, chronische Anämie, akute Anämie | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Rationale: Anämie tritt häufig bei Patienten mit akutem Myokardinfarkt (AMI) auf und trägt zu einer ungünstigen Prognose bei. Der kausale Beitrag der Anämie und deren Einfluss auf den zirkulierenden Stickstoffmonoxid (NO) Pool im Zusammenhang mit der Mortalität nach akutem Myokardinfarkt (AMI) ist unklar.
Zielsetzung: Die Zielsetzung meiner Untersuchungen ist es, die Auswirkungen der akuten und chronischen Anämie auf den akuten Myokardinfarkt zu untersuchen. Insbesondere soll die Rolle, der durch Anämie verursachten, (Dys-) Funktion der roten Blutkörperchen, sowie deren Effekte auf die endotheliale Stickstoffmonoxid- Synthase (eNOS3) auf die linksventrikuläre Funktion nach Ischämie/Reperfusionsschaden überprüft werden. Hypothese: Wir stellen die Hypothese auf, dass der zirkulierende NO-Pool bei Patienten mit AMI und Anämie bei der Aufnahme verändert ist und dass die kardioprotektive Kapazität der Erythrozyten beeinträchtigt ist. Methoden und Resultate: Im Langendorff-Modell wurde der Einfluss von Vollblut oder roter Blutzellen (RBC)-Suspension von anämischen und nicht anämischen Mäusen auf den kardialen Ischämie/Reperfusionsschaden untersucht. Bei den zur Blutspende verwendeten Mäusen wurde eine subakute (3 Tage) und chronische (6 Wochen) Anämie durch repetitiven Blutverlust (<15% des zirkulierenden Blutvolumens) induziert (Ziel-Hämoglobin-Wert <9g/dl). Dabei wurde der Beitrag der eNOS3 nach genetischer Hemmung durch die Zugabe des Vollblutes, als auch reiner RBC-Suspension von Mäusen mit globaler eNOS-/- Eliminierung (eNOS-/- Knockout (KO)) analysiert. Die kardiale linksventrikuläre Kontraktilität wurde anhand des linksventrikulären Druckgradienten (LVDP) und die über den LVDP abgeleitete Geschwindigkeit der Kontraktion (+dp/dt), Geschwindigkeit der Relaxation (-dp/dt) sowie dem linksventrikulär enddiastolische Druck (LVEDP) gemessen. RBCs und Vollblut von Mäusen mit akuter Anämie verringerten die kontraktile Erholung nach myokardialer Ischämie und anschließender Reperfusion. Isolierte RBCs von chronisch anämischen Wildtyp (WT) -Mäusen zeigten keinen wesentlichen Abfall der gemessenen Parameter, wohin gegen das Vollblut von chronisch anämischen WT-Tieren zu einer Verschlechterung der linksventrikulären (LV) Leistung führte. Die Vollblut Proben von eNOS -/- KO Mäusen ohne Anämie waren ebenfalls durch eine Verschlechterung der LV-Kontraktilität nach Ischämie/Reperfusion charakterisiert. während die gleichzeitige Supplementierung der eNOS-/- KO -Mäuse mit dem NO-Donor (DEA NONOate) die negativen Effekte dieser RBC aufheben konnte. Schlussfolgerungen: Zusammenfassend lässt sich sagen, dass eine moderate Blutverlustanämie mit einer Funktionsstörung der roten Blutkörperchen und einem verminderten Gehalt an zirkulierendem Stickstoffmonoxid einhergeht. Sowohl die vaskuläre als auch die kardiale endotheliale Stickstoffmonoxid-Synthase spielen eine entscheidende Rolle bei der Anpassung des Herz-Kreislauf-Systems an die Anämie. Die Funktionsstörungen der roten Blutkörperchen in Verbindung mit einer gestörten eNOS-Funktion könnten zu ungünstigen Ergebnissen bei einem akuten Myokardinfarkt beitragen.Rationale: Anaemia is common in patients with acute myocardial infarction (AMI) and contributes to an unfavorable prognosis. The causal contribution of anaemia and its influence on the circulating nitric oxide (NO) pool in relation to mortality after AMI is unclear. Objective: The aim of my research is to investigate the effects of acute and chronic anaemia on acute myocardial infarction. In particular, the role of anaemia-induced red blood cell (dys-) function and its effect on endothelial nitric oxide synthase (eNOS3) on left ventricular (LV) function after ischaemia/reperfusion injury. Hypothesis: We hypothesise that the circulating NO pool is altered in patients with AMI and anaemia on admission and that the cardioprotective capacity of red cells is impaired. Methods and results: The Langendorff model was used to study the effect of whole blood or red blood cell (RBC) suspension from anemic and non-anemic mice on cardiac ischemia/reperfusion injury. In mice used for blood donation, subacute (3 days) and chronic (6 weeks) anaemia was induced by repetitive blood loss (<15% of circulating blood volume) (target haemoglobin value <9 g/dl). The contribution of eNOS 3 was analysed after genetic inhibition by the addition of whole blood, as well as pure red blood cell (RBC) suspension from mice with global eNOS-/- elimination (eNOS-/- = Knockout). The cardiac left ventricular contractility was assessed using the left ventricular pressure gradient (LVDP), and the derived contraction velocity (+dp/dt), relaxation velocity (-dp/dt), as well as the left ventricular end-diastolic pressure (LVEDP). RBCs and whole blood from mice with acute anaemia reduced contractile recovery after myocardial ischaemia and subsequent reperfusion. Isolated RBCs from chronic anaemic wild-type (WT) mice showed no significant decrease in the measured parameters, whereas whole blood from chronic anaemic WT animals resulted in a deterioration of LV performance. Whole blood samples from eNOS -/- mice without anemia were also characterised by impaired LV contractility after ischaemia/reperfusion. While simultaneous supplementation of the eNOS -/- mice with the NO donor (DEA NONOate) was able to reverse the negative effects of this RBCs. Conclusions: In summary, moderate blood loss anemia is associated with dysfunction of red blood cells and reduced circulating nitric oxide levels. Both vascular and cardiac endothelial nitric oxide synthase play a crucial role in cardiovascular adaptation to anemia. Dysfunction of red blood cells combined with impaired eNOS function may contribute to adverse outcomes in acute myocardial infarction. | |||||||
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| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Bezug: | 2018-2024 | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 30.01.2025 | |||||||
| Dateien geändert am: | 30.01.2025 | |||||||
| Promotionsantrag am: | 27.07.0024 | |||||||
| Datum der Promotion: | 07.11.0024 |
