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Intracellular MMP-2: Role in Normal and Diseased Hearts

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Molecular Defects in Cardiovascular Disease

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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.

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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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  1. Departments of Pediatrics and Pharmacology, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada

    Nermeen Youssef & Richard Schulz

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  1. Nermeen Youssef
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  2. Richard Schulz
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Correspondence to Richard Schulz .

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Editors and Affiliations

  1. St. Boniface General Hospital, Research Centre, Institute of Cardiovascular Sciences, Tache Avenue 351, Winnipeg, R2H 2A6, Manitoba, Canada

    Naranjan S. Dhalla

  2. Jikei University School of Medicine, Shibuya-ku, Ebisu 3-31-6, Tokyo, 150-0013, Japan

    Makoto Nagano

  3. Czech Republic, Institute of Physiology, Academy of Sciences of the, Videnska 1083, Prague, 142 20, Czech Republic

    Bohuslav Ostadal

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Youssef, N., Schulz, R. (2011). Intracellular MMP-2: Role in Normal and Diseased Hearts. In: Dhalla, N., Nagano, M., Ostadal, B. (eds) Molecular Defects in Cardiovascular Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7130-2_2

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