Matrix metalloproteinase-2 mediates cytokine-induced myocardial contractile dysfunction.
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-1 beta, 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.
Gao
Cindy Qun
CQ
Department of Pediatrics, Cardiovascular Research Group, 4-62 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
Sawicki
Grzegorz
G
Suarez-Pinzon
Wilma L
WL
Csont
Tamás
T
Wozniak
Mieczyslaw
M
Ferdinandy
Péter
P
Schulz
Richard
R
D000818:Animals; D002118:Calcium / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000502:physiology*; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D019210:Troponin I / Q000378:metabolism; D000097792:Tissue Inhibitor of Metalloproteinase-4
D002118:Calcium; D003094:Collagen; D016207:Cytokines; D004791:Enzyme Inhibitors; D020778:Matrix Metalloproteinase 2; D019001:Nitric Oxide Synthase; D019714:Tissue Inhibitor of Metalloproteinases; D019210:Troponin I; D000097792:Tissue Inhibitor of Metalloproteinase-4