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The Role of TIMPs in Heart Disease Open Access


Other title
Type of item
Degree grantor
University of Alberta
Author or creator
Kandalam, Vijay S.
Supervisor and department
Kassiri, Zamaneh (Physiology)
Examining committee member and department
Dyck, Jason (Pediatrics)
Clanachan, Alexander (Pharmacology)
Jurasz, Paul K (Pharmacology)
Schulz. Richard (Pharmacology)
Lindsey, Merry L (Medicine)
Department of Physiology

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Heart disease is a leading cause of morbidity and mortality in the world with a growing prevalence in a variety of manifestations. Many of the events that occur in the heart during the progression of disease have been explored to identify a causative mechanism to develop effective treatments and possibly a cure for heart disease. There is a growing body of evidence demonstrating the necessity for adaptive remodeling of the extracellular matrix (ECM) for proper cardiac function in response to disease through balanced regulation of its structure. Cardiac ECM serves as a structural framework for the myocardium, and its integrity is maintained by the function of matrix metalloproteinases (MMPs) which are kept under control by their physiological inhibitors, Tissue Inhibitor of Metalloproteinases (TIMPs). A balance between the MMPs and TIMPs is important for optimal degradation and replacement of the ECM either in physiological ECM turnover or in adverse ECM remodeling in disease. The research presented in this thesis consists of our investigation of the role of two highly expressed TIMPs in the heart, TIMP2 and TIMP3, in response to two common models of human heart disease. Mice lacking TIMP2 or TIMP3 were subjected to myocardial infarction, while the outcome of TIMP2 deficiency was also studied in response to cardiac pressure overload. Myocardial infarction led to different outcomes in the TIMP2-/- and TIMP3-/- mice. While TIMP3-/- mice exhibited elevated rates of left ventricular rupture incidence and severely compromised survival, as well as significant cardiac dysfunction, lack of TIMP2 exacerbated cardiac function without compromising survival compared to parallel wildtype mice. Following pressure overload, TIMP2-/- mice showed left ventricular dilation and dysfunction, hypertrophy and fibrosis which we found to be linked to impaired ECM-myocyte connection due to excess degradation of integrin-1 via excess activity of membrane-type 1 MMP (MT1-MMP). We have therefore identified important and distinct roles for these TIMPs in heart disease. The results presented in this thesis are important contributions to the study of the role of ECM remodeling in the adaptive cardiac response to injury, as demonstrated through a wide variety of physiological, histological, and molecular analyses of the development of heart disease in each model. These findings provide novel evidence identifying distinct mechanisms or pattern of events associated with TIMP2 and TIMP3 that can alter the current understanding of the role of each TIMP in the development and progression of heart disease.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Kandalam V, Basu R, Abraham T, Wang X, Soloway PD, Jaworski DM, Oudit GY, Kassiri Z. Timp2 deficiency accelerates adverse post-myocardial infarction remodeling because of enhanced mt1-mmp activity despite lack of mmp2 activation. Circ Res. 2010;106:796-808Kandalam V, Basu R, Moore L, Fan D, Wang X, Jaworski DM, Oudit GY, Kassiri Z. Lack of tissue inhibitor of metalloproteinases 2 leads to exacerbated left ventricular dysfunction and adverse extracellular matrix remodeling in response to biomechanical stress. Circulation. 2011;124:2094-2105Kandalam V, Basu R, Abraham T, Wang X, Awad A, Wang W, Lopaschuk GD, Maeda N, Oudit GY, Kassiri Z. Early activation of matrix metalloproteinases underlies the exacerbated systolic and diastolic dysfunction in mice lacking timp3 following myocardial infarction. Am J Physiol Heart Circ Physiol. 2010;299:H1012-1023

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File title: PhD Prefatory Thesis FINAL VK 25Sept2012+
File title: The heart of creatures is the foundation of life, the Prince of all, the sun of their microcosm, from where all vigor and strength does flow
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