The Role of TIMPs in Heart Disease

  • Author / Creator
    Kandalam, Vijay S.
  • 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.

  • Subjects / Keywords
  • Graduation date
    Fall 2012
  • 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
  • Supervisor / co-supervisor and their department(s)
  • Examining committee members and their departments
    • Clanachan, Alexander (Pharmacology)
    • Jurasz, Paul K (Pharmacology)
    • Dyck, Jason (Pediatrics)
    • Lindsey, Merry L (Medicine)
    • Schulz. Richard (Pharmacology)