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Title: The regionality of cardiac beta-2-adrenoceptor signalling
Author: Wright, Peter
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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The dysfunction of the apical myocardium is observed following chronic exposure to catecholamines, or after acutely stressful scenarios, in the syndrome of Takotsubo cardiomyopathy. The physiological functions of the β2AR were assessed via measurement of cell shortening; β2AR-cAMP signalling was assessed by FRET microscopy, comparing cells from the apical and basal myocardium. The effects of pre-stimulation of the β2AR with high levels of endogenous catecholamines were investigated to simulate pathological scenarios. The structure of the cellular membranes of cells from different myocardial regions was assessed and manipulated to investigate their role in β2AR signalling. An improved animal model of the regional pathology in Takotsubo was investigated using ovariectomized female rats. Apical cardiomyocytes are sensitized to β2AR stimulation, displaying larger increases in inotropy and lusitropy in comparison to basal cells. This was not due to differences in cAMP levels induced by β2AR within the cell cytosol. Differences were apparent in the amount of cAMP reaching the RII-PKA domains (the main arbiters of cellular inotropy and lusitropy). β2AR-cAMP signalling was discovered to be more persistent in the apical cardiomyocytes. Basal cardiomyocytes were found to have a larger number of caveolae within their membranes, caveolae have been demonstrated to modulate β2AR. Following the disruption of caveolar domains via chelation of cholesterol, apical and basal responses to β2AR stimulation were equalized; inhibition of phosphodiesterase 4 had the same effect. Catecholamine pre-stimulation reduced β2AR responses; adrenaline pre-stimulation exerts a more Gi-dependent desensitization than noradrenaline. Female rats are shown to be relatively protected from the effects of adrenergic overstimulation and ovariectomized female rats suffer acutely high mortality. Cells from different regions of the myocardium may control their receptor signalling in different ways to produce desirable physiological activity. In settings of pathology this phenomena may leave certain regions vulnerable to damage.
Supervisor: Gorelik, Julia ; Harding, Sian E. ; Lyon, Alexander R. Sponsor: Imperial College London
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available