Perhexiline is a metabolic modulator considered to be an alternative pharmacotherapeutic agent in heart failure (HF), a debilitating condition characterised by severe metabolic disturbances (i.e. impaired substrate utilisation and energy production) in which morbidity and mortality are high. However, perhexiline therapy requires regular plasma monitoring, which is clinically unattractive. Moreover, its exact cardioprotective mechanism(s) remains unknown. The work in this thesis aimed to investigate the protective effects and underlying molecular mechanism(s) of perhexiline ex vivo, in Langendorff-perfused mouse hearts and in vivo, in the abdominal aortic constriction model of HF, and to determine whether the effects could be replicated by the novel perhexiline derivative, fluoroperhexiline-1 (FPER-1), which has better pharmacokinetics. Ex vivo, 2 μM perhexiline or 10 μM FPER-1 perfusion increased cardiac contractility and relaxation pre-ischaemia and improved post-ischaemic haemodynamics and hypercontracture magnitude. This involved enhancing the contractility-relaxation pathway (phospholamban (PLB) deactivation) pre-ischaemia and improving glucose metabolism (pyruvate dehydrogenase (PDH) activation and glycogen synthase kinase 3αβ (GSK3αβ) deactivation) during ischaemia. In vivo, 4-week gavage with 70 mg/kg perhexiline or FPER-1 attenuated hypertrophy and cardiac remodelling at end-diastole whilst decreasing the expression of uncoupling protein 3 (UCP3), a redox-sensitive protein. Additionally, perhexiline alone improved systolic function (i.e. improved left ventricular ejection fraction and fractional shortening) in parallel with PLB deactivation. Taken together these results provide novel evidence that perhexiline protects the heart against ischaemic injury and delays progression from hypertrophy to failure by metabolic and non-metabolic (PLB) mechanisms, most of which were replicated by FPER-1.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:760382 |
| Date | January 2018 |
| Creators | Noordali, Hannah |
| Publisher | University of Birmingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://etheses.bham.ac.uk//id/eprint/8503/ |
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