Abstract
Post-myocardial infarction remodelling dictates the prognosis and long-term survival of patients suffering a myocardial infarction. The infarcted myocardium elicits an inflammatory response; pro-inflammatory and anti-inflammatory monocytes sequentially infiltrate the infarct and give rise to macrophages; which contribute to the clearance of the cellular debris, and release matrix metalloproteinases and their endogenous tissue inhibitors that promote the extracellular matrix turnover. Under the influence of intricate pro-inflammatory and anti-inflammatory stimuli, cardiac fibroblasts become activated and synthesise extracellular matrix, therefore promoting wound healing.It was hypothesised that distinct pro-inflammatory and anti-inflammatory macrophage subsets have differential effects on cardiac fibroblast activation and the subsequent cardiac fibrosis. Consequently, the role of matrix metalloproteinases in post-myocardial infarction remodelling, and the intercellular communication between macrophages and cardiac fibroblasts were investigated.
Matrix metalloproteinases were differentially expressed in the macrophage subset secretomes, and investigations in a mouse model of atherosclerosis-associated cardiac remodelling emphasised their divergent roles on coronary plaque progression and associated cardiac fibrosis, highlighting the need for selective therapeutic approaches to target unstable atherosclerosis alongside adverse cardiac remodelling.
In vitro experiments showed that cardiac fibroblast activation was suppressed by the anti-inflammatory macrophage secretome, compared to the pro-inflammatory secretome. The findings revealed the chemokine CXCL10 as a potential mediator of these effects through its cognate receptor, CXCR3. Cathepsin Z activity, from the pro-inflammatory macrophages abrogated CXCL10 effects. Furthermore, in a mouse model of myocardial infarction, CXCL10 and cathepsin Z were abundant in macrophage-rich regions of the infarcts and their expression reduced over time, as did CXCR3-positive cardiac fibroblasts.
Pro-inflammatory and anti-inflammatory macrophages are pivotal regulators of post-myocardial infarction remodelling, through release of divergent matrix metalloproteinases and modulating cardiac fibroblast activation. In this thesis, mechanistic insights, and the beneficial potential of CXCL10/CXCR3 signalling are described, and a CXCL10-enhancing intervention emerges as a promising treatment for reducing maladaptive cardiac fibrosis.
| Date of Award | 24 Jan 2023 |
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| Original language | English |
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| Supervisor | Sarah J George (Supervisor), Jason L Johnson (Supervisor) & Raimondo Ascione (Supervisor) |