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The Role of TIMP3 in Diabetic Nephropathy, Cardiac and Vascular Diseases Open Access


Other title
abdominal aortic aneurysm
extracellular matrix
Type of item
Degree grantor
University of Alberta
Author or creator
Basu, Ratnadeep
Supervisor and department
Zamaneh Kassiri, Physiology
Examining committee member and department
Lopaschuk,Gary (Pharmacology)
Sean, McMurtry (Medicine)
Light, Peter (Pharmacology)
Jones, Jeffrey (Cardio-thoracic surgery)
Seubert, John M (Pharmacology)
Department of Physiology

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Chronic diseases such as diabetes, cardiovascular and renal diseases are major health concerns globally. Cardiovascular diseases with diabetes comprise more than 50% of all deaths attributed to non-communicable diseases worldwide. Acquiring more than one of these diseases at the same time results in poorer prognosis compared to any individual disease. Pathological changes in cellular metabolism and extracellular matrix (ECM) remodelling that result in structural and functional damage are among the common and essential mechanisms that underlie diabetic nephropathy, diabetic cardiomyopathy, focal and systemic vascular diseases. ECM is the structural framework of an organ, and maintaining its integrity is essential for optimal structure and function of the cardiovascular and the renal system. A balance in the function of matrix metalloproteases (MMPs) and their four physiological inhibitors (TIMPs 1-4) is required for optimal ECM turnover. This balance is disrupted in pathological conditions. In addition to being a potent inhibitor of a number of MMPs, TIMP3 is the only ECM-bound TIMP whereby it can exert tissue-specific effects. TIMP3-deficiency has been linked to several cardiovascular and renal diseases, and this effect has been shown to be organ specific and stimulus dependant. We found that TIMP3 was protective in diabetic nephropathy without any contribution to diabetic cardiomyopathy, diastolic dysfunction associated with myocardial metabolic changes and impaired calcium handling. We found a novel role of TIMP3 in both focal (Abdominal aortic aneurysm, AAA) and systemic (Hypertension) vascular pathologies associated with ECM remodelling. In response to Ang II, TIMP3-deficiency resulted in a pathologically suppressed hypertensive response due to excess degradation of vascular ECM which culminated to development of AAA upon prolonged exposure. Targeting MMP2 alone in TIMP3-/- mice exacerbated AAA with heightened inflammation and increased MMP9, however, a broad spectrum MMP inhibitor proved to be a successful approach in preventing AAA. In summary, my thesis explores the essential and optimal role of TIMP3 in the context of pathological ECM remodeling in cardiac, vascular and kidney diseases.
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
Basu R, Kassiri Z. Extracellular matrix remodeling and abdominal aortic aneurysm. Journal of Clinical and Experimental Cardiology. 2013
R, Lee J, Morton JS, Takawale A, Fan D, Kandalam V, Wang X, Davidge ST, Kassiri Z. Timp3 is the primary timp to regulate agonist-induced vascular remodelling and hypertension. Cardiovascular research. 2013;98:360-371
R, Lee J, Wang Z, Patel VB, Fan D, Das SK, Liu GC, John R, Scholey JW, Oudit GY, Kassiri Z. Loss of timp3 selectively exacerbates diabetic nephropathy. American journal of physiology. Renal physiology. 2012;303:F1341-1352
R, Fan D, Kandalam V, Lee J, Das SK, Wang X, Baldwin TA, Oudit GY, Kassiri Z. Loss of timp3 gene leads to abdominal aortic aneurysm formation in response to angiotensin ii. The Journal of biological chemistry. 2012;287:44083-44096
R, Oudit GY, Wang X, Zhang L, Ussher JR, Lopaschuk GD, Kassiri Z. Type 1 diabetic cardiomyopathy in the akita (ins2wt/c96y) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function. American journal of physiology. Heart and circulatory physiology. 2009;297:H2096-2108

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