Matrix metalloproteinase-2 contributes to ischemia-reperfusion injury in the heart

Background-Matrix metalloproteinases (MMPs) contribute to collagen degradation and remodeling of the extracellular matrix after myocardial infarction; however, their role in myocardial dysfunction immediately after ischemia and reperfusion is unknown. Methods and Results-We measured the release of MMPs into the coronary effluent of isolated, perfused rat hearts during aerobic perfusion and reperfusion after ischemia. Aerobically perfused control hearts expressed pro-MMP-2 and MMP-2, as well as an unidentified 75-kDa gelatinase. These enzymes were also detected in the coronary effluent, After 20 minutes of global no-flow ischemia, there was a marked increase in pro-MMP-2 in the coronary effluent that peaked within the first minute of reperfusion, The release of pro-MMP-2 into the coronary effluent during reperfusion was enhanced with increasing duration of ischemia and correlated negatively with the recovery of mechanical function during reperfusion (r(2)=0.99). MMP-2 antibody (1.5 to 15 mu g/mL) and the inhibitors of MMPs doxycycline (10 to 100 mu mol/L) and o-phenanthroline (3 to 100 mu mol/L) improved whereas MMP-2 worsened the recovery of mechanical function during reperfusion, Conclusions-These results show that acute release of MMP-2 during reperfusion after ischemia contributes to cardiac mechanical dysfunction. The inhibition of MMPs may be a novel pharmacological strategy for the treatment of ischemia-reperfusion injury.