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Cardiovascular Research 2003 57(2):426-433; doi:10.1016/S0008-6363(02)00719-8
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Matrix metalloproteinase-2 mediates cytokine-induced myocardial contractile dysfunction

Cindy Qun Gaoa, Grzegorz Sawickib, Wilma L Suarez-Pinzonc, Tamás Csontb, Mieczyslaw Wozniakd, Péter Ferdinandye and Richard Schulza,b,*

aDepartment of Pediatrics, Cardiovascular Research Group, 4-62 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, Canada T6G 2S2
bDepartment of Pharmacology, Cardiovascular Research Group, 4-62 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, Canada T6G 2S2
cDepartment of Medicine, Cardiovascular Research Group, 4-62 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, Canada T6G 2S2
dDepartment of Clinical Chemistry, Medical University of Wroclaw, Wroclaw, Poland
eDepartment of Biochemistry, Cardiovascular Research Group, University of Szeged, Szeged, Hungary

* Corresponding author. Tel.: +1-780-492-6581; fax: +1-780-492-9753. richard.schulz{at}ualberta.ca

Objective: Pro-inflammatory cytokines depress myocardial contractile function by enhancing peroxynitrite production, yet the mechanism by which peroxynitrite does this is unknown. As matrix metalloproteinases (MMPs) can be activated by peroxynitrite and can proteolytically cleave troponin I in hearts, we determined whether this occurs in cytokine-induced myocardial dysfunction. Methods: Isolated working rat hearts were perfused with buffer containing interleukin-1β, interferon-{gamma}, and tumor necrosis factor-{alpha}. Results: Cytokines induced a marked decline in mechanical function during 60–120 min of perfusion. This decline was accompanied by increased myocardial inducible NO synthase activity and perfusate dityrosine (a marker of peroxynitrite), compared to control hearts. Before the decline in mechanical function there was enhanced MMP-2 activity in the perfusate. This was accompanied by decreased tissue levels of MMP-2, tissue inhibitor of matrix metalloproteinases-4 and troponin I in cytokine-treated hearts. The collagen content of the heart was not affected by cytokine treatment. A neutralizing anti-MMP-2 antibody or the MMP inhibitors Ro31-9790 or PD166793 attenuated the decline in myocardial function. Moreover, the MMP-2 antibody prevented the decline in myocardial MMP-2 and troponin I levels. Conclusions: Myocardial contractile dysfunction caused by pro-inflammatory cytokines results in MMP-2 activation and a decline in tissue inhibitor of matrix metalloproteinases-4 in the heart. Troponin I is also a target for the proteolytic action of MMP-2 during acute heart failure triggered by pro-inflammatory cytokines. Inhibition of MMPs may be a novel pharmacological strategy for the treatment of acute inflammatory heart disease.

KEYWORDS Contractile function; Cytokines


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