The Role of Thymosin Beta 4 in the Endogenous Epicardial Response Post-Myocardial Infarction

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