Imbalance between tissue inhibitor of metalloproteinase-4 and matrix metalloproteinases during acute myocardial [correction of myoctardial] ischemia-reperfusion injury.
BACKGROUND
We have previously reported that matrix metalloproteinase-2 (MMP-2) contributes to myocardial ischemia-reperfusion injury by degradation of troponin I, a regulatory element of the contractile proteins. MMP activities are also tightly regulated by tissue inhibitors of metalloproteinase (TIMPs). The change in TIMPs during acute myocardial ischemia-reperfusion injury is not clear.


RESULTS
Isolated rat hearts were perfused either aerobically for 75 minutes or subjected to 15, 20, or 25 minutes of global, no-flow ischemia followed by 30 minutes of aerobic reperfusion. During reperfusion after ischemia, there was a rapid, enhanced release of TIMP-4, the most abundant TIMP in the heart, into the coronary effluent, as shown both by reverse zymography and Western blot. There was a negative correlation between the recovery of cardiac mechanical function and the release of TIMP-4 during reperfusion in hearts subjected to different durations of ischemia. Immunogold electron microscopy revealed a close association of TIMP-4 with the sarcomeres in aerobically perfused hearts. Moreover, TIMP-4 was present only in thin myofilaments prepared from aerobically perfused hearts but not in ischemic-reperfused hearts. An enhanced MMP activity was shown in ischemic-reperfused hearts by in situ zymography.


CONCLUSIONS
Loss of TIMP-4 from the cardiac myocyte leads to an increase in net myocardial MMP activity that contributes to acute myocardial stunning injury.
Schulze
Costas J
CJ
Department of Pharmacology, University of Alberta, Edmonton, Alberta, T6G 2S2 Canada.
Wang
Wenjie
W
Suarez-Pinzon
Wilma L
WL
Sawicka
Jolanta
J
Sawicki
Grzegorz
G
Schulz
Richard
R
D008841:Actin Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D000208:Acute Disease; D000818:Animals; D004789:Enzyme Activation; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000378:metabolism*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D015427:Reperfusion Injury / Q000378:metabolism*; D012518:Sarcomeres / Q000378:metabolism / Q000648:ultrastructure; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*; D000097792:Tissue Inhibitor of Metalloproteinase-4
D020782:Matrix Metalloproteinases; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4