Effect of hypoxia on cardiac metabolism and function in the type 2 diabetic heart

Thesis

Type 2 diabetic patients have impaired cardiac ischaemia-reperfusion recovery and higher rates of mortality following a myocardial infarction. Hypoxia is a key component of ischaemia and therefore, this thesis is aimed to investigate the effect of hypoxia on metabolism and contractile function of the type 2 diabetic heart. In combination with high fat feeding, different doses of streptozotocin (STZ) (15, 20, 25 and 30 mg/kg) were used to determine the optimal dose needed for induction of diabetes in male Wistar rats. A novel type 2 diabetic model was developed and characterised by hyperinsulinaemia, hyperglycaemia and dyslipidaemia. The effects of chronic hypoxia were investigated by housing diabetic rats in a hypoxic chamber (11% O2) for 3 weeks. Results showed that the HIF signalling pathway was not impaired in diabetic hearts. PPARα targets (MCAD, UCP3 and PDK4) were downregulated by chronic hypoxia in control hearts but not in diabetic hearts, suggesting PPARα overactivation in diabetic hearts. Acute hypoxic perfusions (16 minutes normoxia, 36 minutes hypoxia and 20 minutes reoxygenation) were performed to investigate the effect of acute hypoxia on metabolism and cardiac function. Diabetic hearts had impaired metabolic response to acute hypoxia, associated with decreased cardiac function during acute hypoxia and reoxygenation. In the final study, sulfo-N-succinimidyl oleate (SSO), a FAT/CD36 inhibitor was administered prior to acute hypoxia to modulate metabolism in diabetic hearts. The previously seen maladaptation of diabetic hearts to acute hypoxia was improved by SSO. In diabetic hearts, SSO increased glycolysis during acute hypoxia, and normalised fatty acid oxidation and decreased triglyceride deposition upon reoxygenation, associated with improved cardiac function at the end of experiment compared to untreated diabetic hearts. In conclusion, the elevated lipid metabolism contributed to metabolic inflexibility in diabetic hearts, which is associated with the impaired response to hypoxia, and the inhibition of lipid metabolism was associated with improved cardiac function in diabetic hearts following hypoxia.

Authors: Mansor, LS

• DOI: 10.5287/ora-z67kan0dw
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford