The involvement of camkii in myocardial ischaemia-reperfusion injury

CaMKII acts as a second messenger to Ca2+ signals within the cardiac myocyte. Cellular stresses such as ischaemia and subsequent reperfusion perturb the normal physiological oscillations of Ca2+ to cause an escalating concentration which damages the cell. CaMKII has been implicated as an injury signal during such cellular conditions. However, there are discrepancies as to whether CaMKII is a possible mechanism of ischaemic preconditioning as its inhibition can abrogate or improve the protective effect of preconditioning. This thesis investigated the effects of CaMKII inhibition in models of ischaemia-reperfusion (I-R) injury. It was hypothesised that CaMKII promotes irreversible injury caused by acute myocardial infarction (AMI), but would also have a beneficial role in mediating cardioprotection by ischaemic preconditioning. This work has demonstrated that: i) in an ex vivo rat heart model of regional I-R injury, CaMKII promoted irreversible injury but is not a feasible target for reperfusion therapy as only a pre-ischaemic intervention reduced myocardial infarction; ii) CaMKII activation was not a pre-requisite for protection with ischaemic preconditioning, although an additive protective effect of CaMKII inhibition and ischaemic preconditioning was possible; iii) models of simulated I-R or oxidative stress in the H9c2 cells did not involve CaMKII activity; iv) isolated cardiac myocytes paced at 1Hz and subjected to simulated I-R do not engage a significant amount of CaMKII activity. These studies substantiate the involvement of CaMKII during ischaemic injury and establish that it does not play a substantial role in ischaemic preconditioning. It highlights the characteristics of the kinase within in vitro models of I-R injury. Understanding CaMKII role in I-R may underpin the development of future therapeutic strategies for the management of AMI.