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Nitric oxide signaling in cardiac development, function and disease

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Title: Nitric oxide signaling in cardiac development, function and disease
Authors: Vanezis, Konstantinos
Item Type: Thesis or dissertation
Abstract: A variety of roles have been attributed to Nitric Oxide (NO) in the cardiovascular system. During development, exposure of mouse embryonic stem cells to high levels of NO has been shown to promote cardiomyocyte differentiation through activation of transcription factors such as Nkx2.5. In adults, NO has been implicated in control of blood pressure and regulation of cardiac contractility. In disease, it is evident that elevated levels of NO can have a protective effect during myocardial infarction. ADMA and L-NMMA regulate NO biosynthesis by endogenously inhibiting Nitric Oxide Synthases (NOS). DDAH (1 and 2) enzymes metabolise ADMA in order to regulate the production of NO. The aims of this PhD thesis are (1) to identify the role of NO levels during development of the cardiovascular system and (2) to identify the role of the Ddah2 gene during an ischemia/reperfusion injury to the myocardium. Treatment of mouse embryonic stem cells during differentiation with ADMA reduced NO biosynthesis and showed significantly lower expression of cardiac associated markers and endothelial cell markers. This decrease in cardiac differentiation was accompanied by an increase in Runx1, an important hematopoietic marker. Our findings suggest that reduced NO levels guide differentiating cells towards haematopoiesis by parallel reduction of endothelial and cardiac cell formation. Global Ddah2-/- mouse hearts that underwent a global ischemia/reperfusion injury showed significantly higher tissue survival when compared to WT hearts. Gene expression of iNOS and eNOS genes was elevated in Ddah2-/- hearts along with other cellular survival markers. In an attempt to repeat our observations, WT and Ddah2-/- adult cardiomyocytes were isolated and underwent a hypoxia/normoxia treatment. Analysis of cardiomyocytes, showed no increase in hypoxia associated markers such as Glut1 and Ddah1 gene suggesting that either Ddah2-/- cardiomyocytes do not sense hypoxia or that they do not need to induce a hypoxic response to low oxygen levels. This work provides novel insights into the role of NO in cardiac differentiation and Ddah2 gene as a potential therapeutic target for ischemia/reperfusion injuries of the myocardium.
Content Version: Open Access
Issue Date: Sep-2016
Date Awarded: Mar-2017
URI: http://hdl.handle.net/10044/1/68532
DOI: https://doi.org/10.25560/68532
Supervisor: Leiper, James
Sponsor/Funder: British Heart Foundation
Department: Institute of Clinical Sciences
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses



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