Dr Paul Spiers

The primary objectives, in the group of Dr Spiers, centre on the study of molecular and cellular alterations associated with cardiovascular remodelling; a fundamental event in the development and progression of congestive heart failure. In particular, efforts to delineate the intracellular signalling pathways linking neurohormonal balance (eg. sympathetic stimulation) with a group of key regulators of matrix remodelling (metalloproteinases (MMPs)), is our primary focus.

An integral part of this study includes investigations into the role of ß blockers and how specific receptor subtypes influence ventricular remodelling through specific MMPs.

Indeed, the implications of specific receptor subtypes is of great interest as a recent clinical trial reports a favoured survival profile in those receiving carvedilol (non-selective a and a1- antagonist) compared with metoprolol (selective ß1-antagonist).

We have shown that carvedilol (a/ß-AR antagonist), included in the treatment regimen of patients with heart failure, attenuates MMP-9 activity, suggesting a switch to a less degradative phenotype (Figure 1).Indeed, initial results indicate a direct coupling between the adrenergic and matrix metalloproteinase systems in an endothelial ‘like’ cell line (Figure 2). Since gelatinase MMPs are particularly implicated in the remodelling processes of the myocardium during the development of heart failure, we are currently investigating the effects of adrenergic stimulation on MMP-9 promoter activity in ventricular cardiomyocytes. Work in our group during recent months has focused on the validation of a specific cell line (H9C2) as an appropriate model to address signalling mechanism in cardiomyocytes (Figure 3), and in collaboration with Dr Yuri Volkov/ Dr Tony Davies, we are currently addressing questions to delineate the intracellular signalling mechanism coupling adrenoceptors to MMP-9 expression using high content analysis. In the next year we will develop this system to specifically target questions relating to Ca2+ signalling, apoptosis and contractile function directly in cardiomyocytes following hypertrophic remodelling.

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