The prevention of heart failure in our aging population has become a healthcare
priority. As part of the normal aging process patients have been shown to develop age-related myocardial fibrosis, which is characterized by excess deposition and a lack of
clearance of extracellular matrix (ECM) proteins, contributing to the development of
heart failure. The increase in ECM proteins is caused by an imbalance between the
following: (1) collagen biosynthesis by fibroblasts, (2) post-synthetic collagen processing
(cross-linking) which stabilizes collagen, and (3) collagen degradation.
The focus of this thesis lays mainly on collagen biosynthesis and processing, and
how interrupting these can affect the overall balance of collagen in the myocardium. The
two main objectives of this thesis lay in 1 – characterizing the role of a key pro-fibrotic
signal in the TGFβ pathway, connective tissue growth factor (CTGF), in hypertension
induced myocardial fibrosis development, and 2 – investigating the role of lysyl oxidase
(LOX), an enzyme involved in the crosslinking of collagen that has been implicated in
age-related myocardial fibrosis development.
This thesis provides novel evidence that CTGF regulation is an important step in
the early stages of myocardial fibrosis development through regulating new collagen
synthesis and that CTGF is produced as a downstream mediator of TGFβ after AngII
exposure not directly through AngII-AT1R signaling. Additionally, novel evidence is
presented that LOX inhibition reduces age-related myocardial fibrosis and that the
decrease in collagen protein content observed after LOX inhibition is associated with a
significant decrease in new pro-collagen 1 mRNA synthesis. This suggests that LOX
inhibition also inhibits new collagen synthesis by an unknown mechanism. Overall, these
studies have contributed new mechanistic knowledge about myocardial fibrosis
development and explored potential therapeutic strategies aimed at interrupting collagen
homeostasis, which are key to understanding myocardial fibrosis development.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:NSHD.ca#10222/50386 |
| Date | 14 April 2014 |
| Creators | Rosin, Nicole |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
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