Abstract

Hypoxia-inducible factor (HIF) plays a pivotal role in the cellular response to reduced oxygen availability. HIF activity is regulated by two families of oxygen sensitive enzymes; the prolyl hydroxylase domain (PHD) family, and factor-inhibiting HIF (FIH1). FIH1 is thought to be an essential regulator of metabolism but its role in the heart is unknown.

Mice with a null mutation in the FIH1 gene (FIH1-/-, n≥5) had 18% lower body weight (p<0.02) than wild type littermate controls (WT, n≥6), but normal total cardiac mass. Right ventricular mass determined via MRI was 25% greater in FIH1-/- hearts (p<0.01). Cine MRI revealed a 15% reduction in stroke volume in FIH1-/- hearts, from 27.4±2.3 µl in WT to 23.4±1.5 µl in FIH1-/- (p<0.05). Impaired contractility was also observed in individual myocytes (sarcomere shortening was 3.01%±0.20% in FIH1-/- compared to 3.92%±0.17% in WT, p<0.05) and was associated with reduced Ca2+ transient amplitude (fura-2 ratio 0.21±0.02 and 0.29±0.02 for FIH1-/- and WT respectively, p<0.05).

Glycolytic flux (µmol/min/g) was significantly higher in Langendorff perfused FIH1-/- hearts (1.17±0.04) than WT (0.79±0.12, p<0.05) although no changes in lactate efflux were detected. There were no differences in pyruvate dehydrogenase kinase 1 and 4 protein expression and citrate synthase activity (µmol/min/mg) was similar for both WT (1.01±0.02) and FIH1-/- (0.96±0.03) hearts.

Our data suggest a novel role for FIH1 in modulating cardiac contractility and metabolism, with FIH1 ablation producing cardiac effects comparable to those associated with activation of the hypoxic signalling pathway.