Najam, Osman; (2023) Exploring the role of cardiac mast cells in acute myocardial infarction and ischaemia-reperfusion injury. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Mast cells are immune cells derived from pluripotent progenitor cells of the bone marrow that mature under the influence of the c-kit ligand and stem cell factor. Cardiac mast cells are known to be involved in many disease processes including plaque rupture, ischaemia post myocardial infarction and myocardial remodelling after infarction. Myocardial infarction (MI) is defined as decreased or complete cessation of blood flow in one or more coronary arteries supplying the myocardium, resulting in irreversible myocardial cell death, usually due to prolonged ischaemia. The deleterious effects of mast cells are thought to be due to a combination of the primary mediators which are found within the secretory granules, and secondary mediators which are generated upon activation. Evidence suggests a clear and important detrimental role of cardiac mast cells in myocardial infarction. However, the extent to which mast cell inhibition confers cardioprotection and the ideal timing to instigate such a therapeutic intervention is unclear. Mast cells release multiple mediators upon activation, one of which is histamine. Histamine is a known vasoconstrictor, and it is yet to be determined whether it has a detrimental impact in relation to no-reflow phenomena. In addition, it is yet to be determined whether cardioprotection due to mast cell inhibition occurs independently of ischaemic preconditioning (IPC), and whether there may be additive protection using a multi-targeted approach. I therefore aimed to characterise the role of cardiac mast cells in MI and ischaemia-reperfusion injury. Using an ex-vivo Langendorff model of global ischaemia, I report that stabilisation of cardiac mast cells prior to ischaemia reduces the myocardial infarct size, independent of IPC. The use of concurrent IPC therapy provided additional protection. When mast cells were degranulated prior to the ischaemic insult, there was reduction in infarct size suggesting that any potential pharmacological therapy needs to be administered prior to reperfusion. When IPC was given to these degranulated mast cells, there was further cardioprotection suggesting that cardioprotection via mast cell inhibition may be due to either an IPC-independent pathway or that IPC pre- 6 treatment does not fully protect against potential damage caused by mast cells. PI3K-regulated signalling events appear to play an important role in mast cell biology such as mast cell growth, differentiation, activation, and survival. I therefore investigated the role of PI3K-α in cardioprotection by using a pharmacological PI3K-α agonist (UCL-TRO-1938). PI3K-α agonism prior to myocardial infarction showed cardioprotective properties. Finally, I describe the use of the endothelial fluorescent dye Thioflavin S to identify regions of no-reflow for the first time in an ex-vivo model. I also described that by stabilising mast cells prior to global ischaemia, the degree of no-reflow may be reduced suggesting a potentially therapeutic target for this process which to date has no definitive therapy. In summary, my thesis describes how mast cells contribute to ischaemic injury after myocardial infarction, and inhibiting mast cell activation confers cardioprotection, which is additive to IPC. Histamine, a major component of mast cell granules appears to play an important role in myocardial damage and no-reflow phenomena. Finally, use of a multi-targeted approach appears to be beneficial, and research is needed to explore this further.

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