Hydrogen sulfide (H2S) is the simplest endogenously produced thiol and has an indispensable role in cardiovascular homeostasis. It has been shown that exogenous H2S supplementation protected the heart against myocardial ischaemia/reperfusion injury through a mechanism which is yet to be defined. In this thesis, it was hypothesised that controlled application of thiol/H2S donors at reperfusion would mitigate acute myocardial infarction. We sought to characterise the cardioprotection and molecular targets of three H2S donors (mesna, GYY4137 (a slow-releasing, non-mitochondrial targeted H2S donor) and AP39 (a mitochondria-targeting H2S donor)). This characterisation was conducted using a broad range of experimental models and techniques including anaesthetised rat model of ischaemia/reperfusion injury, Western blotting and mitochondrial studies using isolated cardiomyocyte mitochondria, namely subsarcolemmal and interfibrillar mitochondria. Mesna did not limit infarct size when it was given pre-ischaemia or at reperfusion. GYY4137 and AP39 significantly limited infarct size when given specifically at the time of reperfusion through different mechanisms. Cardioprotection established by GYY4137 was mediated mainly by triggering of PI3K/Akt/GSK-3β signalling at reperfusion with partial dependency on eNOS activity. Selective mitochondrial delivery of H2S at reperfusion using AP39 had no effect on Akt, eNOS, GSK-3β and ERK1/2. In isolated mitochondria, AP39 inhibited Ca2+-sensitive opening of PTP in subsarcolemmal and interfibrillar mitochondria through attenuation of mitochondrial reactive oxygen species generation. The studies presented in this thesis provided novel mechanistic insights into cardioprotection by H2S. These studies suggest that targeted delivery of H2S represents a novel and effective adjunctive therapy to ameliorate the injurious effects of reperfusion which contribute to acute myocardial infarction.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:709606 |
| Date | January 2016 |
| Creators | Karwi, Qutuba |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/99908/ |
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