Intracellular action of matrix metalloproteinase-2 accounts for acute myocardial ischemia and reperfusion injury.
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.


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.
Wang
Wenjie
W
Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
Schulze
Costas J
CJ
Suarez-Pinzon
Wilma L
WL
Dyck
Jason R B
JR
Sawicki
Grzegorz
G
Schulz
Richard
R
D008841:Actin Cytoskeleton / Q000737:chemistry; D000818:Animals; D003593:Cytoplasm / Q000201:enzymology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D016253:Microscopy, Immunoelectron; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000209:etiology; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism / Q000648:ultrastructure; D009924:Organ Culture Techniques; D011233:Precipitin Tests; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014336:Troponin / Q000378:metabolism; D019210:Troponin I / Q000032:analysis / Q000378:metabolism*
D011480:Protease Inhibitors; D014336:Troponin; D019210:Troponin I; D020778:Matrix Metalloproteinase 2