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

  • Author / Creator
    Basu, Ratnadeep
  • 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.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Department of Physiology
  • Supervisor / co-supervisor and their department(s)
    • Zamaneh Kassiri, Physiology
  • Examining committee members and their departments
    • Jones, Jeffrey (Cardio-thoracic surgery)
    • Seubert, John M (Pharmacology)
    • Sean, McMurtry (Medicine)
    • Light, Peter (Pharmacology)
    • Lopaschuk,Gary (Pharmacology)