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Permanent link (DOI): https://doi.org/10.7939/R3BW2P

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Intracellular regulation of matrix metalloproteinase-2 activity: the roles of caveolin-1 and troponin I phosphorylation Open Access

Descriptions

Other title
Subject/Keyword
heart
ischemia-reperfusion
troponin I
caveolin
matrix metalloproteinase
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Chow, Ava Kalyca
Supervisor and department
Schulz, Richard (Paediatrics and Pharmacology)
Examining committee member and department
Daniel, Edwin E. (Pharmacology)
Kassiri, Zamaneh (Physiology)
Bernatchez, Pascal (Anesthesiology, Pharmacology and Therapeutics)
Baksh, Shairaz (Paediatrics)
Department
Medical Sciences - Paediatrics
Specialization

Date accepted
2010-09-01T16:23:45Z
Graduation date
2010-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Matrix metalloproteinase‐2 (MMP‐2) was recently revealed to have targets and actions within the cardiac myocyte. In ischemia/reperfusion (I/R) injury, MMP‐2 is activated and degrades troponin I (TnI) and α‐actinin. The regulation of intracellular MMP‐2 activity is relatively unknown and is thus the subject of this thesis. The localization of MMP‐2 in caveolae of endothelial cells suggests that caveolin‐1 (Cav‐1) may play a role in regulating MMP‐2. Whether Cav‐1 is responsible for regulating MMP‐2 in the heart is unknown. A Cav‐1 knockout mouse model was used to explore the role Cav‐1 may play in the regulation of MMP‐2 activity. The initial studies found that MMP‐2 and Cav‐1 were co‐localized in cardiomyocytes and that MMP‐2 activity in Cav‐1‐/‐ hearts was markedly enhanced. Additionally, the caveolin scaffolding domain inhibited MMP‐2 activity in a concentration‐dependent manner. To explore whether increased MMP‐2 in Cav‐1‐/‐ hearts translates to impaired cardiac function, Cav‐1+/+ and Cav‐1‐/‐ isolated working hearts were physiologically challenged with increasing increments of left atrial preload followed by increasing concentrations of isoproterenol. Cav‐1‐/‐ hearts show similar or better cardiac function compared to Cav‐1+/+ hearts following preload challenge or β‐adrenergic stimulation in vitro, and this appears unrelated to changes in MMP‐2. Though the function of Cav‐1‐/‐ hearts appears similar to that of Cav‐1+/+ hearts during physiological situations, whether this is the case during I/R injury is not known. Cav‐1+/+ and Cav‐1‐/‐ isolated working mouse hearts exposed to global, no‐flow ischemia showed no functional differences. However, Cav‐1‐/‐ hearts had significantly higher levels of both TnI and α‐actinin following I/R than Cav‐1+/+ hearts. Post‐translational modifications of the intracellular MMP‐2 substrates could alter susceptibility to MMP‐2 proteolysis. Isolated working mouse hearts were exposed to isoproterenol and/or I/R injury to examine the phosphorylation status of TnI. Isoproterenol and I/R both result in the phosphorylation of TnI, however, isoproterenol lead to a more highly phosphorylated form of TnI than that observed in hearts exposed I/R alone. These and subsequent studies will further reveal the molecular mechanisms that underlie the complex interactions between Cav‐1 and MMP‐2. This may eventually lead to a novel avenue of therapeutic intervention for heart diseases.
Language
English
DOI
doi:10.7939/R3BW2P
Rights
License granted by Ava Chow (akchow@ualberta.ca) on 2010-08-31T21:11:12Z (GMT): 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 the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein 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.
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