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Title: Remodelling of the cardiac caveolar domain in heart failure and its putative influence on beta adrenergic signalling
Author: Norman, Ruth Anne Astley
ISNI:       0000 0004 6349 8264
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2016
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Over 500,000 people in the UK have heart failure (HF). After an initial insult to the heart, sympathetic drive increases which leads to detrimental remodelling of cardiac β-adrenergic receptors (βAR) and further cardiac dysfunction. The main βAR expressed in the heart are the β1AR and β2AR. In heart failure, remodelling is characterised by reduced β1AR density, desensitisation of the remaining β1AR and aberrations of normal βAR signal compartmentalisation. Caveolae, flask-shaped lipid rafts, are present in most cells including cardiac myocytes and are characterised by the presence of caveolin and cavin proteins. Caveolar proteins create distinct micro-domains within the membrane and play a key role in compartmentalisation of signalling from both the β1AR and β2AR. Isolated reports of changes in caveolar structure and proteins in HF have implications for β-AR signalling, however the full array of caveolar protein changes in HF has not previously been assessed. Here we establish how the expression and membrane location of β-AR cascade and caveolar proteins changes in rat models of right ventricular (RV) and left ventricular (LV) failure induced by monocrotaline and aortic banding, respectively. For the RV model, we examined changes in β-AR responsiveness, and tested the potential for reversing functional and caveolar remodelling using a common LV therapy (the β-blocker metoprolol). Quantitative analyses of caveolar protein expression in myocyte and myocardial samples was also carried out using custom-designed calibrating peptides (CavCATs). Both HF models showed a reduction in caveolar protein expression, with protein redistribution also found in the RV model. Decreased expression of β-AR signalling proteins (β1AR, adenylyl cyclase) accompanied by increased expression of inhibitory proteins (Gαi, GRK2) was also observed in both models, with some remodelling of membrane distribution. β-blocker treatment in RV failure partially recovered expression of caveolar and β-AR cascade proteins. Cardiac β1AR responsiveness was reduced in RV failure and again, this was partially recovered by β-blocker treatment. Quantitative work highlights the importance of studying non muscle-specific caveolar protein isoforms in the cardiac myocyte given e.g. similar expression of Cav 3 and Cav 1 in these cells. Caveolae are dynamic membrane compartments which change in HF. This work suggests that caveolar changes affect β-AR signalling protein membrane location, which contributes to aberrations of signalling which (in the case of RV failure) can be reversed by β blockers.
Supervisor: Calaghan, Sarah C. ; White, Ed Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available