Figure 5: Elevated FAs in IR Decrease Hypoxic Succinate Concentrations Required for HIF-1α Stabilization

(A) HIF-1α protein levels following acute hypoxia in control (HC) and IR (HIR) HL-1 cardiomyocytes with the proteasome inhibitor MG132. (B) HIF-1α protein levels in hypoxic IR cells with or without the HIF hydroxylase inhibitor dimethyloxalylglycine (DMOG). (C) In ischemic perfused hearts, HIF-1α protein levels correlate positively with myocardial succinate levels. (D) Succinate concentrations following hypoxia in cells cultured in control medium (HC), IR medium (HIR), and control medium supplemented with 500 μmol/l palmitate (HPal) or 500 μmol/l oleate (HOle). (E and F) HIF-1α protein levels and succinate concentrations in hypoxic cells in the presence of the glycolysis inhibitor 2-deoxyglucose (2DG), the malate-aspartate shuttle inhibitors phenylsuccinate and amino-oxyacetate (PS and AOA), and the succinate dehydrogenase inhibitor dimethylmalonate (DMM). (G and H) HIF-1α protein levels and succinate concentrations in hypoxia in IR cells, with or without the cell permeable succinate donor dimethyl fumarate (DMF). *p < 0.05 versus hypoxic control, #p < 0.05 versus hypoxic insulin resistant. Abbreviations as in Figure 4.