Abstract
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. 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. 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.
Highlights
Ischaemic heart disease (IHD) is the leading cause of death globally, accounting for over a million deaths annually.[1]
Immunoblotting of whole cell lysate further confirmed an increase in hypoxia inducible factor (HIF)-1α protein levels, and this corresponded with an increase in HKII in the purified mitochondrial fraction (Figure 1B)
A number of experimental studies have reported that normoxic HIF-1α stabilisation using non-specific pharmacological prolyl hydroxylase (PHD) inhibitors or genetic manipulation of HIF-1α or PHD can protect the heart from acute ischaemiareperfusion injury (IRI)
Summary
Ischaemic heart disease (IHD) is the leading cause of death globally, accounting for over a million deaths annually.[1]. Various experimental studies have suggested that the stabilisation of hypoxia-inducible factor-1 (HIF-1) under normoxic conditions may confer tolerance against acute myocardial IRI.[2,3,4,5,6,7] the actual mechanism through which HIF-1 mediates its cardioprotective effect is unknown. Pharmacological inhibition of the MPTP at this time has been demonstrated in experimental studies[8,9,10] and one clinical study[11] to reduce MI size by 40-50%. Whether the stabilisation of HIF-1 protects the heart against acute IRI by inhibiting MPTP opening has not previously been investigated. We demonstrate for the first time that normoxic stabilisation of HIF-1 protects the heart against IRI by limiting MPTP opening through a metabolic switch, and that mitochondrial HKII is partially required for HIF-1 in maintaining mitochondrial integrity
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
