116 Matrix metalloproteinase inhibition attenuates reperfusion injury, independently of and additive to mitochondrial permeability transition pore inhibition

While matrix-metalloproteinase (MMP) inhibitors appear to protect against myocardial ischaemia/reperfusion injury, the mechanisms are poorly understood. We hypothesised that cardioprotection resultant from MMP inhibition is independent of mitochondrial permeability transition pore (mPTP), the end-effector of ischaemic postconditioning (iPOC). In ex-vivo and in-vivo mouse hearts, we investigated whether the MMP inhibitor, ilomostat (0.25 μmol/l), at the onset of reperfusion, could engender protection in the absence of cyclophillin-D (CyPD), an initiator of mPTP opening, against injurious ischaemia/reperfusion. We have previously demonstrated that CyPD knockout (KO) hearts have inherent resistance to ischaemia/reperfusion injury, and cannot be further protected by either pre or post conditioning regimen. Therefore to further attenuate infarction in this model would require a mechanism independent of the mPTP. We found that ilomastat attenuated infarct size in wild type (WT) animals (37%±2.8% to 22%±4.3%, equivalent to ischaemic post conditioning (iPostC—6 cycles of 10sec reperfusion/ischaemia), 27%±2.1%, p