Intracellular MMP-2: Role in Normal and Diseased Hearts

Chapter

Abstract

Matrix metalloproteinase (MMP)-2 is an abundant protease found in all cells of the heart and is well known for its role in extracellular matrix remodeling. Its biological actions in physiological processes such as angiogenesis and heart development, as well as in cardiac pathologies such as ischemia–reperfusion injury and heart failure, have been significantly expanded, as it is now understood to have specific targets and actions inside the cardiac myocyte. MMP-2 localizes to the nucleus, mitochondria, caveolae, and especially the sarcomere of cardiac myocytes. 72-kDa MMP-2 is directly activated by oxidative stress, especially by peroxynitrite, in a mechanism not requiring proteolytic removal of its propeptide. Studies from our laboratory have identified novel intracellular substrates for it including troponin I, titin, myosin light chain-1, α-actinin, glycogen synthase kinase-3β, and poly (ADP-ribose) polymerase. The proteolysis of the sarcomeric proteins by MMP-2 rapidly follows reperfusion of ischemic heart muscle and contributes to myocardial stunning injury, which can be ameliorated by MMP inhibitors. Other intracellular targets are yet to be discovered, and each provides new mechanisms by which MMP-2 can affect cardiac contractile function. MMP inhibitors may become therapeutic drugs for the treatment of heart diseases associated with enhanced oxidative stress.

Keywords

Matrix metalloproteinase-2 Extracellular matrix Gelatinase Oxidative stress Phosphorylation TIMP MMP inhibitors Caveolin-1 Doxycycline Peroxynitrite Troponin I Titin Myosin light chain-1 Cytoskeleton α-Actinin Glycogen synthase kinase-3β Sarcomere Ischemia–reperfusion Glutathiolation Stunning 

Notes

Acknowledgments

We thank Dawne Colwell for ­graphics.Studies from the Schulz lab have been generously ­supported by the Canadian Institutes for Health Research, the Heart and Stroke Foundation of Alberta, NWT and Nunavut, and the Alberta Heritage Foundation for Medical Research.

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Departments of Pediatrics and Pharmacology, Cardiovascular Research Centre, Mazankowski Alberta Heart InstituteUniversity of AlbertaEdmontonCanada

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