Abstract 12184: Matrix Metalloproteinase-2 (MMP2) Activity and Myocardial Infarction: Can MMP2 Inhibition Prevent ‘Double-dip’ Dysfuntion from Elective (Surgical) Ischemia-Reperfusion
Matrix metalloproteinase-2 (MMP2), a gelatinase involved in cell structure degradation, may have an important role in acute cardiac ischemia-reperfusion injury. We investigated whether MMP2 is involved in heart dysfunction when previously infarcted hearts were subjected to additional elective global ischemia (as in cardiac surgery). The left coronary artery of rat hearts was surgically occluded for 7 days. Hearts were then excised and Langendorff-perfused (20 min) before 30 min global ischemia and 60 min reperfusion. An MMP2 inhibitor, 1,10-phenanthroline (100 µM), was added to perfusate/reperfusate (10 min) before and after ischemia; also, cardioplegia with or without inhibitor (60 min ischemia) was examined. Mechanical function (left ventricular developed pressure: LVDP) of the heart was continuously monitored. MMP2 activity was measured in the initial 6 ml of coronary reperfusate (by zymography), and in heart tissue at different reperfusion times (by MMP2 activity assay). Recovery of function (% pre-ischemic LVDP) in infarcted hearts was significantly (p>0.05) lower (22±2%) than non-infarcted (39±2%) or sham (39±3%) hearts. MMP2 activity in infarcted hearts peaked at 5 min reperfusion (1.03 ng/ml/g of protein) and was significantly (p>0.05) higher than non-infarcted hearts (0.576 ng/ml/g). MMP2 release into the coronary effluent was higher in infarcted than non-infarcted hearts during baseline perfusion (p>0.05), but did not further increase in infarcted hearts after the additional ischemia. Inhibition of MMP2 activity improved recovery in infarcted hearts to 47±4% (p>0.05). In cardioplegia studies, there was no difference in recovery (42.8±9% vs 45±7%) when inhibitor was only given before and after ischemia. However, addition of inhibitor to both perfusate and cardioplegia was effective in improving outcome (57±6% vs 43±9% in control; best fit analysis, p=0.03). Additional elective global ischemia (as in cardiac surgery) reduced mechanical function in infarcted hearts and increased MMP2 activity. MMP2 inhibition ameliorated cardiac dysfunction, suggesting an acute role for MMP2. MMP2 inhibition throughout ischemia (as an additive to cardioplegia) was required for improved cardioprotection of infarcted hearts.
- © 2012 by American Heart Association, Inc.