The roles played by the transcriptional regulators PPARalpha, HIF-1alpha and SIRT1 in the control of cardiac metabolism

Thesis

The failing heart is characterised by altered energy substrate metabolism, which is a potential target for the development of new heart failure treatments. Transcriptional regulatory proteins orchestrate long-term control of cardiac metabolism by altering gene expression patterns. Thus, these proteins may be viable targets for such metabolic therapies. The work in this thesis aimed to increase understanding of the roles and interactions of three important transcriptional regulators, PPARα, HIF-1α and SIRT1 in the heart, using a combination of animal and cell culture models. Wild type (controls) and PPARα knockout mice were fasted for 24 hours, with PPARα shown to be non-essential for mediating metabolic flexibility through pyruvate dehydrogenase (PDH) down-regulation. Aged male and female PPARα knockout mice had increased cardiac PDH flux in the fed and fasted states relative to controls, indicating a role for PPARα in aging-associated metabolic changes. Subsequently, the HL-1 cardiomyocyte cell line was characterised as an in vitro model of cardiac metabolism, with studies of hypoxia and hypoxia mimetic treatment demonstrating mitochondrial metabolic changes of a HIF-1α-dependent or independent nature. Male Wistar rats were treated with nicotinamide, to investigate its ability to modulate cardiac SIRT1 activity through increasing tissue NAD levels. Nicotinamide treatment altered cardiac metabolism by decreasing PDH activity and modulating mitochondrial metabolic pathways, as well as increasing cardiac SIRT1 activity after 8 weeks of treatment. To assess the interactions between SIRT1, PPARα and HIF-1α, rats were subjected to fasting, high fat feeding or hypoxia treatments. Cardiac SIRT1 activity was respectively increased and decreased by fasting and high fat feeding treatments in rats, and hypoxic exposure decreased SIRT1 activity, demonstrating cross talk between the activities of PPARα, HIF-1α and SIRT1 in the heart. The results presented here increase knowledge of cardiac transcriptional regulation, which is important for our understanding of how manipulating cardiac metabolism may enable the development of therapies to improve energy metabolism in cardiac disease states.

Authors: Ambrose, L

• Publication date: 2014
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: Oxford University, UK
• Language: English
• Keywords: Cardiac metabolism
• Subjects: Metabolism; Physiology and anatomy