Molecular Mechanisms of Myocardial Fibrosis Development

Abstract

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.