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Cardioprotection afforded by targeting guanylyl cyclase during early reperfusion

Bice, Justin S. 2012. Cardioprotection afforded by targeting guanylyl cyclase during early reperfusion. PhD Thesis, Cardiff University.
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Abstract

Guanylyl cyclase - cyclic guanosine monophosphate (cGMP) signalling has been demonstrated to play an important role in the endogenous cardioprotective signalling of the myocardium during early reperfusion. It is proposed that infarct limitation is afforded by elevating cGMP and activating protein kinase G and its distal targets. It was hypothesised that increasing the activity of soluble guanylyl cyclase (sGC) would limit myocardial ischaemia-reperfusion injury. Primarily using the rat isolated perfused heart method, the experiments reported in this thesis investigate the role of exogenous targeting of sGC during early reperfusion, specifically exploring targeting different redox states of the enzyme and their effects on myocardial infarct size. The novel sGC stimulator BAY 41-2272 and activator BAY 60-2770 were selected to investigate this hypothesis. Both administration of BAY 41-2272 and BAY 60-2770 during early reperfusion significantly limited infarct size compared to controls. This was associated with elevated total tissue cGMP levels. Inhibition of nitric oxide could not completely abrogate this protection, but exogenous perfusion of nitric oxide along with BAY 41-2272 showed synergistic action. Oxidation of the prosthetic haem group by ODQ abrogated the protection afforded by BAY 41-2272 but potentiated the protection afforded by BAY 60-2770. Targeting both the reduced and oxidised forms of sGC together did not afford additive protection, in fact it reduced the protection afforded compared to the individual treatments. Preliminary data also suggest that targeting the particulate form of guanylyl cyclase increases activity of Akt signalling during early reperfusion suggesting common signalling between soluble and particulate guanylyl cyclase. These data suggest that targeting sGC during early reperfusion can afford cardioprotection by limiting infarct size. The relationship between cGMP elevation and infarct size needs to be investigated further. Nevertheless, these studies suggest that sGC may be a tractable target for the therapeutic management of acute myocardial infarction.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: Ischaemia; Reperfusion; Soluble guanylyl cyclase; Infarction; Guanosine-3’,5’-cyclic monophosphate; Myocardium
Date of First Compliant Deposit: 30 March 2016
Last Modified: 04 Jun 2017 03:20
URI: http://orca-mwe.cf.ac.uk/id/eprint/19776

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