Mechanisms of cardiac remodeling and failure
Subtitle: role of the tissue inhibitor of matrix metalloproteinase-3.
Published: 2004
Language: eng
Number of pages: 235
Description: TIMPs (tissue inhibitors of metalloproteinases) are complex endogenous biomolecules that contribute to the regulation of tissue architecture and remodeling in both health and disease. Of the four TIMP species, TIMP-3 is unique and its role in the adult heart is undefined. We hypothesized that TIMP-3 plays a key role in initiating, coordinating, and maintaining maladaptive cardiac remodeling in the failing heart. To establish a proof-of-concept that TIMP-3 influences myocardial remodeling and dysfunction, mutant mice lacking TIMP-3 by gene deletion were assessed for altered cardiac structure and function with aging. Cardiomyopathic human and hamster myocardium was similarly assessed for architectural, cellular, and molecular indices of maladaptive remodeling in relation to TIMP-3 expression. The profile of TIMP expression was then assessed in vascular smooth muscle cell-transplanted cardiomyopathic hamster hearts to identify a mechanism through which cell transplantation limits the progression of heart failure. TIMP-3 gene deletion in mice triggered progressive cardiac dilatation and dysfunction consistent with human dilated cardiomyopathy. At the cellular level, loss of TIMP-3 expression resulted in profound cardiac matrix disruption and cell death. At the molecular level, loss of TIMP-3 activated matrix metalloproteinase-9 and the pro-inflammatory TNF-alpha cytokine system. TIMP-3 was reduced in both human and dilated cardiomyopathic hamster myocardium in association with maladaptive cardiac remodeling. In hamster cardiomyopathy, cell transplantation partially restored deficient TIMP-3 and limited maladaptive matrix remodeling. These results suggest that TIMP-3 directly influences matrix homeostasis and cytokine bioactivation in the heart. Altered TIMP-3 expression in the failing heart may directly contribute to maladaptive myocardial tissue remodeling, cardiac dysfunction, and the progression to heart failure. Replacement of deficient TIMP-3 by gene or cell therapy may provide a novel approach to prevent disease progression in patients at risk of heart failure.
Notes: Adviser:  Ren-Ke Li.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 5064.