Matrix metalloproteinase-2 degrades the cytoskeletal protein alpha-actinin in peroxynitrite mediated myocardial injury.
Matrix metalloproteinase (MMP)-2 mediates myocardial ischemia-reperfusion injury which is characterized by enhanced peroxynitrite biosynthesis during early reperfusion. Direct infusion of peroxynitrite into isolated hearts activates MMP-2 prior to the loss in mechanical function. The mechanical dysfunction is prevented by MMPs inhibitors. MMP-2 is also found in the sarcomere of cardiomyocytes where it cleaves troponin I and myosin light chain I. Cytoskeletal proteins such as alpha-actinin, desmin and spectrin are found in close association with the sarcomere and are known to be degraded in ischemia-reperfusion injury. It remains unknown whether these proteins are degraded in peroxynitrite-induced myocardial injury and if cytoskeletal proteins are also targets for MMP-2. Peroxynitrite (80 microM) was infused into isolated rat hearts which led to a delayed onset but rapidly developing decline in mechanical function. The MMPs inhibitor PD-166793 or the peroxynitrite scavenger glutathione prevented the decline in cardiac function. At the end of perfusion, alpha-actinin levels were decreased by 45+/-3% in peroxynitrite-infused hearts as compared to control hearts; however, this was normalized to that of control hearts with either PD-166793 or glutathione. Cardiac desmin and alphaII spectrin levels were unaltered following peroxynitrite infusion. alpha-Actinin and to a lesser extent desmin are susceptible to in vitro proteolysis by MMP-2 whereas spectrin is resistant. Cardiac dysfunction induced by peroxynitrite involves degradation of alpha-actinin that may be mediated by the proteolytic action of MMP-2.
Sung
Miranda M
MM
Department of Pharmacology, Cardiovascular Research Group, 4-62 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
Schulz
Christina G
CG
Wang
Wenjie
W
Sawicki
Grzegorz
G
Bautista-López
Norma L
NL
Schulz
Richard
R
D000185:Actinin / Q000378:metabolism*; D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003893:Desmin / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism / Q000502:physiology*; D008840:Microfilament Proteins / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000139:chemically induced* / Q000378:metabolism*; D030421:Peroxynitrous Acid; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D033921:Vesicular Transport Proteins / Q000378:metabolism
D003598:Cytoskeletal Proteins; D003893:Desmin; D008840:Microfilament Proteins; C422208:Sptan1 protein, rat; D033921:Vesicular Transport Proteins; D000185:Actinin; D030421:Peroxynitrous Acid; D020778:Matrix Metalloproteinase 2