Published Online
on April 21, 2003

A more recent version of this article appeared on May 20, 2003

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Submitted on January 31, 2003
Accepted on February 4, 2003

Imbalance Between Tissue Inhibitor of Metalloproteinase-4 and Matrix Metalloproteinases During Acute Myocardial Ischemia-Reperfusion Injury

Costas J. Schulze MD, Wenjie Wang MD, PhD, Wilma L. Suarez-Pinzon MSc, Jolanta Sawicka MSc, Grzegorz Sawicki PhD, and Richard Schulz PhD^*

From the Departments of Pharmacology (C.S., W.W., J.S., G.S., R.S.), Pediatrics (R.S.), and Medicine (W.L.S.-P.), Cardiovascular Research Group, University of Alberta, Edmonton, Canada.

^* To whom correspondence should be addressed. E-mail: richard.schulz{at}ualberta.ca.

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.

Methods and 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.

Key words: ischemia • reperfusion • inhibitors • metalloproteinases

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