Circulation. 2002;106:1543-1549
Published online before print August 26, 2002, doi: 10.1161/01.CIR.0000028818.33488.7B
Published online before print August 26, 2002, doi: 10.1161/01.CIR.0000028818.33488.7B
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(Circulation. 2002;106:1543.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Intracellular Action of Matrix Metalloproteinase-2 Accounts for Acute Myocardial Ischemia and Reperfusion Injury
From the Departments of Pharmacology (W.W., C.J.S., G.S., R.S.), Pediatrics (J.R.B.D., R.S.), and Medicine (W.L.S.-P.), University of Alberta, Edmonton, Alberta, Canada.
Correspondence to Dr Richard Schulz, Departments of Pediatrics and Pharmacology, 4-62 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. E-mail richard.schulz{at}ualberta.ca
Background— Matrix metalloproteinases are best recognized for their ability to degrade the extracellular matrix in both physiological and pathological conditions. However, recent findings indicate that some of them are also involved in mediating acute processes such as platelet aggregation and vascular tone. The acute contractile defect of the heart after ischemia-reperfusion may involve the proteolytic degradation of the thin filament protein troponin I; however, the protease responsible for this remains obscure.
Methods and Results— Here we report that matrix metalloproteinase-2 is colocalized with troponin I within the thin myofilaments of cardiomyocytes in ischemic-reperfused hearts and that troponin I is a novel intracellular target for proteolytic cleavage by matrix metalloproteinase-2. Inhibition of matrix metalloproteinase-2 activity prevented ischemia-reperfusion-induced troponin I degradation and improved the recovery of mechanical function of the heart.
Conclusions— These data reveal for the first time a novel molecular mechanism by which matrix metalloproteinase-2 causes acute myocardial dysfunction after ischemia-reperfusion-injury and that matrix metalloproteinase-2 has a biological action within the cell.
Key Words: metalloproteinases • ischemia • reperfusion • troponin
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