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Roles and mechanisms of action of the L-cysteine cystathionine-gamma-lyase hydrogen sulphide pathway in the heart

Elsey, David Jonathan 2009. Roles and mechanisms of action of the L-cysteine cystathionine-gamma-lyase hydrogen sulphide pathway in the heart. PhD Thesis, Cardiff University.

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Abstract

Hydrogen sulphide (H2S) is a naturally occurring gas and originally the primary focus of research was to investigate its toxicity. In 1989 a physiological role of H2S was proposed after endogenous levels were detected in the rat brain and normal human post-mortem tissue. This discovery has led to an explosion of interest in H2S as a biological mediator. Identification of H2S synthesising enzymes in the cardiovascular system has led to a number of studies examining specific regulatory actions of H2S. The hypothesis underlying the studies in this thesis was that H2S synthesising enzymes exist in the myocardium and the resulting H2S provides cardioprotection against ischaemia-reperfusion injury. This was investigated using a broad range of experimental techniques including Langendorff isolated perfused rat heart models, biochemical H2S stimulation and detection assays, PCR, and Western blotting. The principal findings can be summarised as follows: 1. Rat myocardium has the potential to express both CSE and CBS H2S synthesising enzymes, due to the confirmed detection of mRNA. 2. Furthermore it was possible to exogenously stimulate the CSE enzyme, with its substrate L-cysteine, to produce H2S gas which limited infarct size during regional ischaemia-reperfusion. 3. Endogenous H2S levels were up-regulated during ischaemia-reperfusion, consistent with an endogenous protective role within the myocardium. 4. Simple and complex H2S/thiol containing compounds produced cardioprotection during regional ischaemia-reperfusion, with a mechanism that involves PI3k and Akt activation, implicating recruitment of downstream kinases within the RISK pathway. The studies presented have provided a significant advancement in understanding the involvement of H 2S in cardioprotection during ischaemia-reperfusion. It has also raised questions such as the exact mechanism of action of H2S donor/thiol containing compounds and highlighted the need for more robust H2S donors. The scope for H2S as an endogenous mediator also stems beyond that of cardioprotection, as the range of body systems and cell types are continually expanding.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Pharmacy
Subjects: R Medicine > RS Pharmacy and materia medica
ISBN: 9781303189180
Funders: British Heart Foundation
Date of First Compliant Deposit: 30 March 2016
Last Modified: 03 Dec 2014 16:39
URI: http://orca-mwe.cf.ac.uk/id/eprint/55820

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