The Integrative Role of FIH1 in HIF-dependent Oxygen Sensing of Cardiac Cells. (360G-Wellcome-103938_Z_14_Z)

Hypoxic-inducible factor (HIF) plays a pivotal role in the transcriptional response to changes in oxygen availability in mammalian cells. Factor inhibiting HIF (FIH-1) may maintain HIF degradation under mildly reduced oxygen tension. We will investigate the role of FIH-1 in cardiac oxygen sensing using in vivo, ex vivo and in vitro approaches. We hypothesize that hearts of FIH1-/- mice will be sensitized to chronic hypoxic exposure and have abnormal mitochondrial oxygen sensing. Mechanisms of reduced myocardial contractility of FIH1 null heart muscle will be elucidated using single fibre techniques in the light of recent in vivo pilot data. Mice will be subsequently housed in chronic hypoxia. Carbohydrate and fatty acid fluxes would be measured in isolated perfused hearts using dual 14C and 3H radiolabelling. Cardiac function will be assessed in both Langendorff perfused hearts and isolated contracting myocytes. Electronmicroscopy would examine the effects of hypoxia on mitochondrial morphology and cellular location of the HIF proteins. The results would contribute to a greater understanding of the role of FIH-1 in oxygen sensing in cardiac cells and allow assessment of whether targeting FIH-1 may have therapeutic potential in the treatment of ischaemic heart disease.