Dokument: Mechanismen der endothelialen Dysfunktion bei Anämie: Einfluss von reaktiven Sauerstoffspezies, endothelialer Arginase und dysfunktionalen Erythrozyten auf die endotheliale Stickstoffmonoxidsynthase

Titel:

Mechanismen der endothelialen Dysfunktion bei Anämie: Einfluss von reaktiven Sauerstoffspezies, endothelialer Arginase und dysfunktionalen Erythrozyten auf die endotheliale Stickstoffmonoxidsynthase

Weiterer Titel:

Mechanisms of endothelial dysfunction in anemia: influence of reactive oxygen species, endothelial arginase, and dysfunctional erythrocytes on endothelial nitricoxidesynthase

URL für Lesezeichen:

https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=66198

URN (NBN):

urn:nbn:de:hbz:061-20240626-113608-9

Kollektion:

Dissertationen

Sprache:

Deutsch

Dokumententyp:

Wissenschaftliche Abschlussarbeiten » Dissertation

Medientyp:

Text

Autor:

Dahlmann, Paul [Autor]

Dateien:

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Dateien vom 19.06.2024 / geändert 19.06.2024

Beitragende:

Prof. Dr. Kelm, Malte [Gutachter]
PD Dr. med. Florian Simon [Gutachter]

Stichwörter:

Kardiologie, Anämie, Myokardinfarkt, Endothelfunktion, endotheliale Dysfunktion, ROS, Arginase, eNOS, Stickstoffmonoxid,Organbad

Dewey Dezimal-Klassifikation:

600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit

Beschreibungen:

Bei Patienten mit akutem und chronischem Koronarsyndrom wird häufig eine Anämie diagnostiziert. Studien haben belegt, dass eine Anämie die Prognose bei akutem Myokardinfarkt (AMI) verschlechtert. Im Tiermodell wurde gezeigt, dass eine Blutungsanämie die Bildung dysfunktionaler roter Blutkörperchen (RBK) induziert. Bisher ist nicht geklärt, ob neben der RBK-Dysfunktion eine veränderte Endothelfunktion im Zusammenhang mit den anämieassoziierten Komplikationen steht. Eine endotheliale Dysfunktion (ED), definiert durch reduzierte Bioverfügbarkeit von Stickstoffmonoxid (NO), könnte die Prognose von anämischen Patienten mit AMI negativ beeinflussen. Diese Arbeit untersucht die Auswirkung der Anämie auf die Endothelfunktion großer Gefäße. Durch repetitive Blutentnahmen wurde in männlichen C57BL/6J-Mäusen (WT-Mäuse) eine subakute oder chronische Anämie induziert. Im Anschluss wurde die Endothelfunktion der thorakalen Aorta im Organbad quantifiziert. Aorten von subakut und chronisch anämischen Mäusen wiesen im Vergleich zu unbehandelten Mäusen eine reduzierte NO-abhängige Relaxation auf. Die chronische Anämie erhöhte die Empfindlichkeit der glatten Muskulatur (GMZ) gegenüber exogenem NO in Mäusen, die die endotheliale Stickstoffmonoxid-Synthase nicht exprimierten (eNOS-KO). Weder die Deletion der endothelialen Arginase I noch die pharmakologische Inhibition der Arginase I und II hat die Endothelfunktion anämischer Mäuse verbessert. Die Behandlung von chronisch anämischen WT-Mäusen mit dem Antioxidans N-Acetylcystein (NAC) verbesserte die endothelabhängige Relaxation der isolierten Gefäße. In Summe implizieren die Daten, dass die subakute und chronische Anämie über erhöhte Freisetzung von reaktiven Sauerstoffspezies die Induktion einer ED bewirkt hat. Eine gesteigerte Arginaseaktivität scheint nicht in den Pathomechanismus der ED involviert gewesen zu sein. Im zweiten Teil der Arbeit wurde ein Protokoll erarbeitet, um die Interaktion von RBK und dem Endothel messbar zu machen. Aortenringe von WT-Mäusen wurden mit humanen RBK inkubiert. Nach der Inkubation wurde die Endothelfunktion im Organbad quantifiziert. Unterschiedliche Inkubationbedingungen wurden evaluiert und schließlich ein finales Protokoll formuliert. Gemäß diesem Protokoll wurden Gefäße mit RBK von Probanden mit AMI oder mit RBK von gleichalten, gesunden Probanden inkubiert. Nach Inkubation wiesen die Gefäße beider Kohorten eine eingeschränkte Relaxation auf, die auf eine gestörte Interaktion von NO und der löslichen Guanylatcyclase der GMZ hinweisen könnte.

Anemia is frequently observed in patients with acute and chronic coronary syndromes. It is well known that anemia leads to poor prognosis in cases of acute myocardial infarction (AMI). In animal models, hemorrhagic anemia has been shown to induce the formation of dysfunctional red blood cells (RBCs). However, it remains unclear whether the complications related to anemia are restricted to RBC dysfunction or are also associated with systemic alterations of endothelial function. Altered endothelium dependent nitric oxide (NO)-synthesis and associated decreased NO bioavailability are hallmarks of endothelial dysfunction (ED) and might contribute to poor prognosis of AMI in patients with anemia. This thesis outlines anemia-associated ED with a focus on large arteries. Sub-acute and chronic blood loss anemia was induced in C57BL/6J
male mice (WT-mice) through repetitive blood withdrawal. Endothelial function was assessed in the thoracic aorta using tissue organ bath, which demonstrated that aortic rings from both sub-acute and chronic anemic mice showed reduced NO-dependent relaxation compared to non-anemic mice (Sham-mice). In addition, assessment of endothelial function in the aorta of anemic global endothelial nitric oxide-synthase knockout mice (eNOS-KO) demonstrated an enhanced smooth muscle sensitivity to exogenous NO compared to sham eNOS-KO mice. Neither the genetic deletion of endothelial arginase I nor the pharmacological inhibition of arginase I and II improved the endothelial function in anemic mice. The aortic rings from chronic anemic mice supplemented with the antioxidant N-Acetylcysteine showed improved endothelial dependent relaxation responses. In summary, these results imply that both sub-acute and chronic anemia are associated with ED. Enhanced activity of arginases does not appear to be involved in the pathomechanism of ED. Increased production of reactive oxygen species in the aorta might contribute to ED in anemia. The second part of the thesis is aimed to establish a protocol to study the interaction between RBCs and the endothelium. Aortic rings from WT-mice were incubated with human RBCs. Following the incubation, endothelial function was assessed using an organ bath system. Various incubation conditions were evaluated, resulting in a final protocol. Based on the refined conditions, aortic rings were incubated with RBCs collected from both subjects with AMI and age-matched, healthy subjects. After incubation the aortic rings in both groups exhibited impaired relaxation, potentially by affecting the signaling pathway of NO and soluble guanylatecyclase.

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Heinrich-Heine-Universität Düsseldorf

Dokument: Mechanismen der endothelialen Dysfunktion bei Anämie: Einfluss von reaktiven Sauerstoffspezies, endothelialer Arginase und dysfunktionalen Erythrozyten auf die endotheliale Stickstoffmonoxidsynthase