EXAMINATION OF HEPARIN / HEPARAN SULPHATE INTERACTIONS WITH CARDIAC GROWTH FACTORS UPREGULATED DURING ISCHAEMIC HEART DISEASE

Abstract

Heparin, a highly sulphated glycosaminoglycan (GAG), is often used in clinics for its anticoagulant property especially in cases of Ischaemic heart disease (IHD). However, recently, there is an increasing number of studies which highlighted the complications that arise with the use of heparin due to its ability to bind to a wide range of growth factors, eliciting varied biological responses. Heparan sulphate (HS) is a heparin-like GAG which is relatively less sulphated and has negligible anticoagulant activity. Thus, HS does not have the side-effects associated with heparin and could be used as a glycotherapeutic for IHD.

This thesis provides insights on the structural properties of heparin that affect neuregulin-1β (NRG1β)-mediated activities and vascular endothelial cell growth factor (VEGF165)-mediated effects in cardiomyocytes and cardiac microvascular endothelial cells (CMECs) respectively. Furthermore, this thesis provides evidence that heparin: growth factors interactions are distinct, unique and can present us with the relevant information for the development of suitable glycotherapy. In addition, based on our in vitro data, this work has demonstrated the potential of using HS7, a VEGF165-binding HS, as a novel cardiac repair therapy for IHD. HS7 may stimulate cardiac repair by enhancing the activity of endogenous VEGF165 in the ischaemic heart.