Cardioprotective effect of remote ischaemic preconditioning and the role of Early growth response-1 as a master switch regulator

Once the blood supply is restored after heart attack by opening up the coronary artery, the heart is insulted by ischemia-reperfusion (I/R) injury. Direct ischaemic preconditioning has the ability to protect the heart against this injury for a brief period of time. Direct ischaemic preconditioning involves cycles of non-lethal occlusion of the coronary artery and releasing. Preconditioning other organs remote to the heart such as the limbs can protect the heart from I/R injury. This new therapeutic technique, known as remote ischaemic preconditioning (RIPC) is non-invasive and easy to apply compared to direct ischaemic preconditioning. However, we still do not know the mechanism through which RIPC protects the heart. This thesis explores the underlying mechanism of RIPC-induced cardioprotection from myocardial I/R injury, in experimental in vitro and in vivo models. Both intrinsic and extrinsic pathways of apoptosis contribute to cell death during heart attack. This thesis explores the relative contribution of the apoptotic pathways in I/R injury. Moreover, autophagy is associated with myocardial I/R injury sparing effect of direct ischaemic preconditioning and postconditioning. It is hypothesized that autophagy plays a key role in RIPC-mediated cardioprotection and autophagy stimulation provides therapeutic benefit. There is evidence that preconditioning can decrease the level of early growth response-1 (Egr-1), a master regulator highly expressed in heart tissue followed by heart attack. Once Egr-1 is highly expressed, a number of downstream inflammatory signalling molecules get expressed, which are well known to cause myocardial damage. It is shown that Egr-1 downregulation in the hind limb prior RIPC abolishes RIPC-induced cardioprotection. In addition, it augmented certain a number of process that are attenuated by RIPC including apoptosis, cytokine expression. This work identifies a key role for Egr-1 in the signalling mechanism of RIPC through its regulation of a number of crucial downstream genes and cardioprotective pathways. In addition, it identifies IL-6 as a potential mediator of RIPC to mitigate myocardial I/R injury