Advances in pharmacological and interventional strategies for the treatment of ischaemic heart disease and acute myocardial infarction (MI), have paradoxically increased the number of patients living with heart failure. Re-vascularisation of the infarcted myocardium can improve cardiac repair; and thus minimise morbidity and mortality rates in heart failure patients. While a number of re-vascularisation strategies are currently being explored, a major hindrance to successful neovascularisation has been concomitant smooth muscle (SM) support. The epicardium, the epithelial tissue that surrounds the heart, is a developmental source of SM cells (SMCs). Previous work in our lab demonstrated a role for Thymosin Beta 4 (Tβ4) in epicardial activation and systemic SM progenitor differentiation. The aim of this project was to investigate the role of Tβ4 in the endogenous response to MI. I hypothesised that endogenous Tβ4 recapitulates its role during development and activates the adult epicardium post-MI, providing SM support for new vasculature. My data provide evidence that Tβ4 does indeed have a role in the endogenous response post-MI. Tβ4 was found to be upregulated post-MI in the epicardium, and Tβ4 deficiency resulted in a significant reduction in epicardial activation and SM contribution to neovascularisation. A yeast-two-hybrid screen identified Low density lipoprotein receptor-related protein 1 (LRP1) as a potential Tβ4 binding partner. Evidence is further provided of epicardial expression of LRP1 and of its role in epicardial function and neovascularisation during development. Further studies are required to confirm a direct interaction between Tβ4 and LRP1 and to elucidate the precise mechanisms through with the proposed Tβ4-LRP1 interaction may impact epicardial activation and SM differentiation and together contribute to myocardial revascularisation and repair.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:639703 |
| Date | January 2015 |
| Creators | Dube, K. N. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1462079/ |
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