Matrix metalloproteinase-2 degrades the cytoskeletal protein alpha-actinin in peroxynitrite mediated myocardial injury.

Abstract

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.

• Authors: Miranda M Sung, Christina G Schulz, Wenjie Wang, Grzegorz Sawicki, Norma L Bautista-López, Richard Schulz
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 43 Issue 4 Pg. 429-36 (Oct 2007) ISSN: 0022-2828 [Print] England
• PMID: 17854826 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytoskeletal Proteins
• Desmin
• Microfilament Proteins
• Sptan1 protein, rat
• Vesicular Transport Proteins
• Actinin
• Peroxynitrous Acid
• Matrix Metalloproteinase 2

Topics

• Actinin (metabolism)
• Animals
• Cytoskeletal Proteins (metabolism)
• Desmin (metabolism)
• Heart (drug effects, physiopathology)
• Male
• Matrix Metalloproteinase 2 (metabolism, physiology)
• Microfilament Proteins (metabolism)
• Myocardial Reperfusion Injury (chemically induced, metabolism)
• Peroxynitrous Acid
• Protein Binding
• Protein Processing, Post-Translational
• Rats
• Rats, Sprague-Dawley
• Vesicular Transport Proteins (metabolism)