Differential Roles of the Tissue Inhibitors of Matrix Metalloproteinases (TIMPs) in Heart Failure

• Author / Creator

  Takawale, Abhijit, R

• Considering the morbidity and mortality associated with heart failure, there is an increasing demand to develop new therapeutic alternatives for cardiac diseases. Advanced left ventricular remodeling following ischemic and pressure-overload cardiomyopathy causes changes in LV geometry, myocyte size, extracellular matrix and vascular compartments which altogether contribute to heart failure. Normal homeostasis of the myocardial extracellular matrix (ECM) is maintained by enzymes known as matrix metalloproteinases (MMPs), and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). Depending on the type of cardiac injury, an altered balance between MMP/TIMPs exacerbates heart disease and eventually leads to heart failure. The research presented in this thesis identifies novel and differential roles of TIMP1, TIMP3 and TIMP4 in cardiac diseases. We observed that TIMP4 is required for recovery from myocardial ischemia-reperfusion injury through its MT1-MMP inhibitory function since its deficiency caused significantly higher MT1-MMP activity, exacerbation of heart dysfunction and LV remodeling post-I/R. On the other hand, TIMP1 promotes cardiac fibrosis in response to pressure-overload and Ang II infusion) in an MMP-independent manner, by mediating an interaction between CD63 and integrinβ1 in cardiac fibroblasts. Adenoviral delivery of TIMP3 but not TIMP4 improved cardiac function and ameliorated adverse remodeling post-MI. Interestingly, TIMP3 promoted endothelial proliferation and angiogenesis in the infarcted myocardium in a dose-dependent manner. The research described in this thesis reveals the ECM-dependent and ECM-independent functions of TIMPs in heart disease. The differential functions of TIMP1, TIMP4 and TIMP3 in heart failure demonstrate that TIMPs do not always exert a beneficial effect in heart disease, and that their function is not limited to their MMP-inhibitory function. Rather, each TIMP has unique functions depending on the type of cardiac injury and can play differential roles in heart failure.

• Subjects / Keywords

  • Heart Failure,
  • ECM Remodeling,
  • Cardiac fibrosis

• Graduation date

  Fall 2017

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3H98ZT1G

• 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.