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Title: The role of adenosine A2A receptor signalling in cardiac fibrosis
Author: Stockenhuber, Alexander
ISNI:       0000 0004 6060 6311
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Myocardial fibrosis contributes to the pathogenesis of diverse forms of cardiac hypertrophy. Recent evidence suggests a crucial role for purinergic signalling in the formation of tissue fibrosis. In particular, inhibition of adenosine A2A receptors (A2AR) in animal models for hepatic and skin fibrosis resulted in a reduction of fibrosis formation. The specific hypothesis of this investigation was that myocardial stress results in increased interstitial levels of adenosine, which activate cardiac fibroblasts via adenosine A2AR. Accordingly, the specific objective of this investigation was to delineate the role of adenosine A2AR signalling in the development of myocardial fibrosis. In vitro, isolated cardiac fibroblasts demonstrated a significant increase in collagen secretion into CCM upon specific A2AR stimulation. This stimulatory effect was inhibited by the addition of a specific A2AR inhibitor. In vivo, models for cardiac hypertrophy including the transgenic cardiac actin E99K hypertrophic cardiomyopathy model, and a transverse aortic constriction (TAC) model of pressure overload, were investigated as murine models for myocardial fibrosis (MF). In cardiac actin E99K hearts the occurrence of cardiac fibrosis was associated with ventricular dysfunction, as well as energetic perturbations. In addition, a direct linear correlation between myocardial collagen content and interstitial adenosine levels was found in actin E99K hearts upon microdialysis experiments. Crossbreeding of actin E99K and A2AR knock-out (KO) mice resulted in a significant reduction of myocardial collagen content and fibrosis in E99K heterozygous A2AR KO animals compared to E99K heterozygous A2AR wild-type (WT) animals. Further, adenosine A2AR KO mice undergoing transverse aortic constriction demonstrated significantly less fibrosis formation compared to constricted WT mice. This was associated with a significant rescue of cardiac function. In addition, pharmacologic adenosine A2AR inhibition using the antagonist ZM241385 demonstrated a partial rescue of myocardial fibrosis in both TAC and E99K animals. These data suggest that adenosine the A2AR plays a crucial role in the formation of myocardial fibrosis in a variety of cardiac pathologies and that this pathway is susceptible to pharmacologic modulation. A2AR manipulation may contribute to further understanding of pathophysiological pathways in the development and progression of cardiac disease and represents an excellent therapeutic target for clinically available A2AR antagonists.
Supervisor: Ashrafian, Houman ; Watkins, Hugh Sponsor: British Heart Foundation ; Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available