AIMS: Hypoxia-inducible factor-1 (HIF-1) has been reported to promote tolerance 
against acute myocardial ischaemia-reperfusion injury (IRI). However, the 
mechanism through which HIF-1 stabilization actually confers this 
cardioprotection is not clear. We investigated whether HIF-1α stabilization 
protects the heart against acute IRI by preventing the opening of the 
mitochondrial permeability transition pore (MPTP) and the potential mechanisms 
involved.
METHODS AND RESULTS: Stabilization of myocardial HIF-1 was achieved by 
pharmacological inhibition of prolyl hydroxylase (PHD) domain-containing enzyme 
using GSK360A or using cardiac-specific ablation of von Hippel-Lindau protein 
(VHL(fl/fl)) in mice. Treatment of HL-1 cardiac cells with GSK360A stabilized 
HIF-1, increased the expression of HIF-1 target genes pyruvate dehydrogenase 
kinase-1 (PDK1) and hexokinase II (HKII), and reprogrammed cell metabolism to 
aerobic glycolysis, thereby resulting in the production of less mitochondrial 
oxidative stress during IRI, and less MPTP opening, effects which were shown to 
be dependent on HKII. These findings were further confirmed when HIF-1 
stabilization in the rat and murine heart resulted in smaller myocardial infarct 
sizes (both in vivo and ex vivo), decreased mitochondrial oxidative stress, and 
inhibited MPTP opening following IRI, effects which were also found to be 
dependent on HKII.
CONCLUSIONS: We have demonstrated that acute HIF-1α stabilization using either a 
pharmacological or genetic approach protected the heart against acute IRI by 
promoting aerobic glycolysis, decreasing mitochondrial oxidative stress, 
activating HKII, and inhibiting MPTP opening.