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Changes in gene expression are associated with key cardiac pathologies such as end-stage heart failure and hypertrophy, as well as in beneficial cardiac remodelling. We work closely with the Molecular Biology Group and others at the Heart Science Centre in an effort to integrate basic science approaches with clinical studies into the management of heart failure. Our major interest concerns the use of a selective β2 adrenergic receptor (β2-AR) agonist, clenbuterol in the Artificial Heart & Bridge to Recovery programme. Recent evidence suggests that β2 agonists promote beneficial hypertrophy in models of dilated cardiomyopathy (DCM), the most common cause of end-stage heart failure. Clenbuterol is used uniquely at Harefield as part of LVAD support in order to promote beneficial hypertrophy. Our group aims to dissect the molecular pathways involved using a cell culture system in which cardiac myocytes are exposed to clenbuterol. Preliminary evidence suggests that clenbuterol induces phosphorylation of Protein Kinase B/Akt, which has been implicated in both β2-AR mediated hypertrophy and in anti-atrophic pathways. Our work focusses in particular on examining how cardioprotective growth factors such as insulin-like growth factor I (IGF-I) may be activated in response to β2-AR stimulation. IGF-I may be a direct transcriptional target for transcription factors activated in response to clenbuterol binding to the β2-AR and IGF-I protein may then promote hypertrophic growth and/or suppress atrophy.
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