Metalloproteinases in the Development of Hypertension and Cardiac Remodeling

  • Author / Creator
    Wang, Xiang
  • 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.

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  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
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    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.
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  • Institution
    University of Alberta
  • Degree level
  • Department
  • Supervisor / co-supervisor and their department(s)
  • Examining committee members and their departments
    • Sipione,Simonetta (Pharmacology)
    • Schang, Luis (Biochemistry)
    • MacDonald, Justin (Biochemistry & Molecular Biology, Universtiy of Calgary)
    • Stone, James (Biochemistry)
    • Kassiri, Zamaneh (Physiology)