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The Role of Disintegrin and Metalloproteinase 15 (ADAM15) in Myocardial Infarction

  • Author / Creator
    Chute, Michael
  • Ischemic cardiomyopathy remains the primary cause of heart failure worldwide. A disintegrin and metalloproteinases (ADAMs) are a family of membrane-bound proteases with diverse functions. ADAM15 is expressed in the myocardium and is involved in mechanisms associated with ischemic heart disease pathology, however, its function in ischemic heart disease remains unexplored. We investigated if ADAM15 is involved in the remodeling of the left ventricle after a MI was induced. The research presented in this thesis identified the role of ADAM15 in left ventricular remodeling following myocardial infarction. Adult male wildtype (WT) and ADAM15-deficient (Adam15-/-) mice were subjected to myocardial infarction (MI) by permanent ligation of the left anterior descending (LAD) artery. LV structure and function were assessed by echocardiography. Adam15-/- mice exhibited significantly compromised survival post-MI, mainly due to LV rupture. Cardiac contractility was reduced in Adam15-/-- compared to WT-MI mice. Hearts were assessed at 3-days or 1-week post-MI, the start and end of the time period for LV rupture incidents, respectively. Collagen fibers in the scar tissue were distorted and scarce in Adam15-/--MI hearts (second harmonic generation imaging), associated with reduced levels of lysyl oxidase-1 (LOX-1), a major collagen cross-linking enzyme, and expression of fibronectin, a key extracellular matrix (ECM) protein. In vitro adult cardiac fibroblasts from Adam15-/- hearts showed impaired myofibroblast transformation under ischemic conditions iii (hypoxia+nutrition deletion), suggesting attenuated fibroblast activation. In vivo and in vitro molecular analyses revealed that interaction of ADAM15 with p21-activated kinase (PAK1) is required for induction of LOX-1 and fibronectin which are critical in optimal scar formation post-MI. In summary, the research described in this dissertation demonstrates that ADAM15 is required for optimal scar formation following myocardial infarction. ADAM15-deficiency suppresses fibroblast activation and induction of LOX-1 and fibronectin, thereby impairing wound healing post-MI, by preventing FB activation leading to deleterious remodelling and LV rupture.

  • Subjects / Keywords
  • Graduation date
    Spring 2021
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/r3-2epn-1458
  • 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.