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Title: Role of Tissue Inhibitor of Metalloproteinase-2 in Human Cardiac Fibroblast-Mediated Extracellular Matrix Remodeling
Author: Ngu, Janet
Advisor: Fedak, Paul
Keywords: Medicine and Surgery
Issue Date: 30-Apr-2013
Abstract: After a myocardial infarction, extracellular matrix (ECM) dysregulation leads to maladaptive cardiac remodeling that constitutes the basis of development of heart failure. Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) is an endogenous biomolecule that is critical in the maintenance of ECM architecture. Cardiac fibroblasts are the main cell type that regulates ECM homeostasis. This study employed an innovative method of three-dimensional collagen gel assay, which mimics the natural in vivo ECM. We investigated the effect of TIMP-2 on the human cardiac fibroblast-mediated ECM remodeling. TIMP-2 induced differentiation of cardiac fibroblasts into myofibroblasts that are active in collagen synthesis. Concurrently, TIMP-2 induced an increase in the total protease activity within the collagen gel microenvironment. TIMP-2 did not promote a fibrotic response, despite its ability to activate myofibroblasts. These actions appear to be independent of its MMP-inhibitory actions. In conclusion, TIMP-2 promotes ECM homeostasis via simultaneous induction of myofibroblast activation and total protease activity.
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