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Preconditioning decreases ischemia/reperfusion-induced release and activation of matrix metalloproteinase-2
Manoj M Lalu1, Csaba Csonka, Zoltán Giricz
1Cardiovascular Research Group, Department of Pharmacology, University of Alberta, Edmonton, AB, Canada T6G 2S2.
Abstract:
Release and activation of matrix metalloproteinases (MMPs) significantly contribute to myocardial stunning injury immediately after ischemia and reperfusion, however, their role in preconditioning remains unknown. We therefore examined the effects of preconditioning and subsequent ischemia/reperfusion on MMP activity in isolated rat hearts. Hearts were subjected to a preconditioning protocol (three consecutive 5-min periods of global ischemia interspersed with 5 min of reperfusion) followed by 30 min ischemia and 5 min reperfusion. To measure MMP release, coronary effluent was collected: (a) during aerobic perfusion, (b) in reperfusion following each preconditioning ischemia, and (c) during the final reperfusion following test ischemia. MMP-2 activities could be detected by gelatin zymography in the ventricles and coronary effluent samples from the perfused hearts. The levels of MMP-2 activity in the effluent were markedly increased in effluent following test ischemia from control hearts without preconditioning. This was accompanied by a decrease in corresponding tissue MMP activities. Preconditioning significantly decreased the MMP-2 activity in the coronary effluent following test ischemia/reperfusion and preserved the MMP-2 protein content and activity in the myocardium. Our results demonstrate that classic preconditioning inhibits ischemia/reperfusion induced release and activation of MMP-2. These results suggest that preconditioning may exert part of its cardioprotective effects through the reduction of MMP-2 release.
Insights
Classic heart preconditioning significantly reduces matrix metalloproteinase-2 (MMP-2) release and activation following ischemia and reperfusion injury. This suggests MMP-2 inhibition is a key mechanism in preconditioning
Area of Science:
- Cardiovascular Physiology
- Biochemistry
- Cellular Biology
Background:
- Matrix metalloproteinases (MMPs), particularly MMP-2, are implicated in myocardial stunning after ischemia/reperfusion (I/R).
- The role of cardiac preconditioning in modulating MMP activity during I/R injury was previously unknown.
Purpose of the Study:
- To investigate the effect of a classic preconditioning protocol on MMP activity in isolated rat hearts subjected to I/R.
- To determine if preconditioning influences MMP-2 release and activation in response to I/R.
Main Methods:
- Isolated rat hearts underwent a preconditioning protocol (3x 5-min ischemia/5-min reperfusion) followed by 30-min test ischemia and 5-min reperfusion.
- Coronary effluent was collected to measure MMP release via gelatin zymography.
- Tissue MMP activity and protein content were also assessed.
Main Results:
- MMP-2 activity was detected in both ventricles and coronary effluent.
- Control hearts without preconditioning showed increased MMP-2 effluent activity and decreased tissue activity post-I/R.
- Preconditioning significantly reduced MMP-2 activity in the coronary effluent after test I/R.
- Preconditioning preserved myocardial MMP-2 protein content and activity.
Conclusions:
- Classic preconditioning effectively inhibits the ischemia/reperfusion-induced release and activation of MMP-2.
- Reduced MMP-2 release appears to be a significant mechanism contributing to the cardioprotective effects of preconditioning.