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Metalloproteinases in the Development of Hypertension and Cardiac Remodeling Open Access

Descriptions

Other title
Subject/Keyword
Metalloproteinases
cardaic fibrosis
cardiac hypertrophy
Hypertension
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Wang, Xiang
Supervisor and department
Fernandez-Patron, Carlos (Biochemistry)
Examining committee member and department
MacDonald, Justin (Biochemistry & Molecular Biology, Universtiy of Calgary)
Stone, James (Biochemistry)
Schang, Luis (Biochemistry)
Sipione,Simonetta (Pharmacology)
Kassiri, Zamaneh (Physiology)
Department
Department of Biochemistry
Specialization

Date accepted
2013-09-13T13:40:03Z
Graduation date
2013-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Despite many decades of research and drug development, the diseases of the cardiovascular system remain a major health threat in the modern world. Hypertensive cardiac disease is a cardiovascular condition characterized by the co-occurrence of hypertension and pathological cardiac remodeling (hypertrophy and fibrosis). Causative factors of hypertensive cardiac disease range from environmental stress to metabolic morbidities. However, these detrimental factors have a common effector mechanism: the sustained activation of G protein-coupled receptors (GPCRs) due to pathological levels of cognate agonists which elevate systemic blood pressure and promote pathological cardiovascular remodeling. GPCR agonists can trigger the activation of metalloproteinases, including matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs). These metalloproteinases are multifunctional enzymes that transactivate many intracellular signaling pathways including those leading to hypertension and cardiac remodeling. Therefore, MMPs and ADAMs have been widely speculated to be potential treatment targets for hypertensive cardiac disease. In the current studies, we use angiotensin II and adrenoceptor ligands as prototypes of GPCR agonists to gain insights into mechanisms of hypertensive heart disease in rodent models. We determine various new roles played by MMP-2, MMP-7, ADAM-12 and ADAM-17. We demonstrate that: 1. MMP-7 mediates GPCR agonist-induced signaling with MMP-7 inhibition by pharmacological blockade, RNA interference or genetic knockout protecting against hypertensive cardiac remodeling. 2. ADAM-17 also contributes to GPCR agonist-induced cardiac hypertrophy and fibrosis. These effects of ADAM-17 are signaledby ADAM-12, a major effector metalloproteinase in cardiac hypertrophy signaling. 3. MMP-2 contributes to the development of GPCR agonist-induced hypertension such that partial blockade of MMP-2 by inhibitors and RNA interference attenuates angiotensin II-induced hypertension. 4. MMP-2 protects against hypertensive cardiac remodeling. To explain the cardioprotection rendered by MMP-2, we evoke a novel mechanism of negative regulation of the sterol-regulatory element binding protein (SREBP)-2 / 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) pathway of cardiac remodeling. These findings are a major contribution to our current understanding of the cardiovascular biology of metalloproteinases. Our data show the diverse roles of metalloproteinases in hypertensive cardiac disease and the potential and limitations of therapeutic approaches based on metalloproteinase inhibition for management of cardiovascular disease.
Language
English
DOI
doi:10.7939/R37D2QG59
Rights
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
Wang X, Chow FL, Oka T, Hao L, Lopez-Campistrous A, Kelly S, Cooper S, Odenbach J, Finegan B, Schulz R, Kassiri Z, Lopaschuk G, Fernandez-Patron C. MMP-7 and ADAM-12 define a signaling axis in agonist-induced hypertension and cardiac hypertrophy. Circulation. 2009 May 12;119(18):2480-9Wang X, Oka T, Chow FL, Cooper S, Odenbach J, Lopaschuk G, Kassiri Z, Fernandez-Patron C. TACE is a key regulator of agonist-induced cardiac hypertrophy. Hypertension. 2009 Sep;54(3):575-82.Odenbach J, Wang X, Cooper S, Chow FL, Oka T, Lopaschuk G, Kassiri Z, Fernandez-Patron C. MMP-2 mediates angiotensin II-induced hypertension under the transcriptional control of MMP-7 and TACE. Hypertension. 2011 Jan;57(1):123-30.

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