Abstract
Heart failure is a major global health burden. The mechanisms that drive heart failure progression are incompletely understood. NADPH oxidase (Nox) enzymes are considered to play an important role in heart failure biology. The primary function of Nox enzymes’ is to produce reactive oxygen species (ROS). Nox2 and Nox4 are the predominant isoforms in the heart and have been identified as important players in determining whether the heart undergoes adaptive or maladaptive remodelling processes. This thesis builds on established work demonstrating that cardiomyocyte-targeted Nox4 (csNox4-Tg) protects against pathological remodelling during pressure-overload. The aim of this thesis was to identify novel Nox4-driven cardioprotective mechanisms in order to further inform our understanding of heart failure biology and in particular the role of Nox enzymes.The key findings were that csNox4-Tg mouse hearts had a profound remodelling of the cardiac proteome that was maintained during overload-stress. Expression changes involving metabolism and Nrf2-activated pathways were significantly over-represented in csNox4-Tg hearts. Taking these findings further, an increase in the rate of fatty acid oxidation (FAO) was found to be dependent on Nox4. Reliance on FAO was not detrimental to cardiac function and energetics. It was also found that a greater proportion of glucose ended up in branch pathways that are associated with the cellular stress response and biomass generation (i.e. hexosamine biosynthesis, pentose phosphate pathway and serine biosynthesis). Thus there is potential that in the setting of pressure-overload, Nox4 can drive energetic requirements through maintaining FAO whilst providing additional cardioprotection through countering cellular stress and augmenting biomass requirements. The effects of pressure-overload in mice with targeted deletion of Nrf2 in cardiomyocytes confirmed the importance of Nrf2 in cardioprotection. Subsequent generation of mice with cardiomyocyte-targeted over-expression of Nox4 with and without Nrf2 was undertaken in order to begin to explore their cross-talk and to what extent the Nox4-associated metabolic cardioprotective phenotype is reliant on Nrf2.
In conclusion the thesis describes novel studies demonstrating that Nox4 can influence cardiac metabolism, potentially involving the transcription factor Nrf2 that together, may protect the heart against adverse cardiac remodelling. It is hoped that the work presented in this thesis will provide novel insights into Nox4-mediated effects in the heart informing our therapeutic paradigms that one day may lead to more effective treatments for heart failure.
| Date of Award | 2015 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Ajay Shah (Supervisor) & Manuel Mayr (Supervisor) |