The Clinical Translation of Platelet Derived Growth Factor and its Application in Models of Cardiac Dysfunction

Abstract

Cardiovascular diseases remain a leading cause of death world-wide, significant among them is heart failure which has a 5-year mortality rate approaching 50%. Substantial efforts have been made to address the limited regeneration of the adult myocardium post myocardial infarction (MI), however there remains no treatment option to reverse the damage of large MIs. Platelet derived growth factor-AB (PDGF-AB) has been reported to significantly improve cardiac function following MI in murine and porcine models. Whilst these results pose PDGF-AB as a promising novel therapeutic post-MI, its poor scalability and the short biological half-life of this growth factor limits its prospects for clinical translation. To address this, we aimed to develop an alternative to PDGF-AB. Utilising a key region of PDGF we hypothesised that peptide mimetics could replicate the effects of PDGF in vitro and in vivo, whilst addressing its shortcomings.

In this thesis we establish lead candidate peptides JC5 and JC5a, due to their significant effects in vitro assessing known functions of PDGF-AB. The efficacy of JC5 and JC5a was then assessed in vivo using a murine model of acute MI. This demonstrated the efficacy of JC5 and JC5a in significantly improving cardiac function 28 days post-MI.

With the aim of identifying a model of chronic heart failure to test in vivo efficacy of JC5 and JC5a, we validated a reported mouse model of heart failure with preserved ejection fraction (HFpEF). Whilst replicating aspects of the HFpEF phenotype, our results did not show significant changes within the extracellular matrix. We concluded that this model was not appropriate for efficacy testing in the context of our work given the hypothesised mechanism of PDGF-AB.

In conclusion, this work shows the effects of PDGF-AB can be mimicked in vitro and in vivo in a murine model of acute MI providing JC5 and JC5a as alternatives to PDGF-AB as a novel therapy post-MI, preventing the development of heart failure.