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Implications of Intracellular Proteolytic Activation of MMP-2 in the Heart

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Role of Proteases in Cellular Dysfunction

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 8))

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Abstract

Matrix metalloproteinases (MMPs) are a family of metalloproteases comprised of 25 related members, of which 24 are found in mammals. By cleaving their target proteins, MMPs play regulatory roles in signaling events, control the cellular environment, and modulate many bioactive molecules at the cell surface to influence cell behavior. However, MMPs are also localized inside the cell and can cleave intracellular substrates. In the heart, MMP-2 is widely expressed in nearly all cells and plays important roles in a variety of physiological and pathological processes, ranging from heart development to ischemia–reperfusion (I/R) injury that triggers an acute loss in heart contractile function. MMP-2 is abundantly expressed in cardiac myocytes and is directly activated by oxidative stress. This results in the S-glutathiolation of a critical cysteine in the prodomain which removes its coordination to the catalytic zinc and allows access of substrates to its catalytic domain, resulting in the proteolysis of specific sarcomeric and cytoskeletal intracellular proteins. MMP-2 activity is also regulated by its phosphorylation. Intracellular substrates of MMP-2 include troponin I, titin, myosin light chain 1, α-actinin, and glycogen synthase kinase-3β. The hydrolysis of specific sarcomeric and cytoskeletal proteins by MMP-2 contributes to contractile dysfunction after I/R injury pointing towards inhibition of MMP-2 as a possible therapy for the treatment of heart diseases associated with enhanced oxidative stress.

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Acknowledgments

My Kondo was a fellow of the Heart and Stroke Foundation of Canada. Research in the Schulz laboratory is supported by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Alberta NWT and Nunavut, and the National Sciences and Engineering Research Council of Canada.

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Authors and Affiliations

  1. Department of Pediatrics, University of Alberta, Edmonton, AB, Canada

    Marcia Y. Kondo & Richard Schulz

  2. Department of Pharmacology, University of Alberta, Edmonton, AB, Canada

    Marcia Y. Kondo & Richard Schulz

  3. Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada

    Marcia Y. Kondo & Richard Schulz

  4. Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada

    Marcia Y. Kondo & Richard Schulz

  5. WCHRI, University of Alberta, Edmonton, AB, Canada

    Richard Schulz

  6. 4-62 Heritage Medical Research Centre, University of Alberta, Edmonton, AB, Canada, T6G 2S2

    Richard Schulz

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  1. Marcia Y. Kondo
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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 Hosp. Research, Univ. of Ma Institute of Cardiovascular Sciences, Winnipeg, Manitoba, Canada

    Naranjan S. Dhalla

  2. Dept of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, India

    Sajal Chakraborti

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Kondo, M.Y., Schulz, R. (2014). Implications of Intracellular Proteolytic Activation of MMP-2 in the Heart. In: Dhalla, N., Chakraborti, S. (eds) Role of Proteases in Cellular Dysfunction. Advances in Biochemistry in Health and Disease, vol 8. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9099-9_18

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