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(Circulation. 2000;101:1833.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Matrix Metalloproteinase-2 Contributes to Ischemia-Reperfusion Injury in the Heart
From the Departments of Pediatrics (P.-Y.C., R.S.), Pharmacology (P.-Y.C., G.S., W.W., M.W.R., R.S.), and Obstetrics/Gynecology (M.W.R.), University of Alberta, Edmonton, Alberta, Canada, and the Department of Clinical Chemistry, Medical University, Wroclaw, Poland (M.W.).
Correspondence to Dr Richard Schulz, Departments of Pediatrics and Pharmacology, 462 HMRC, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada. E-mail richard.schulz{at}ualberta.ca
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 (r2=0.99). MMP-2 antibody (1.5 to 15 µg/mL) and the inhibitors of MMPs doxycycline (10 to 100 µmol/L) and o-phenanthroline (3 to 100 µmol/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.
Key Words: ischemia • reperfusion • metalloproteinases • myocardium
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