The role of hypoxia-inducible factor-1 (HIF-1) in cardioprotection

Background - Preconditioning confers strong resistance to ischaemia with strong links to hypoxic-inducible factor-1 (HIF-1) although the exact molecular mechanisms remain unknown. We investigated how HIF-1 might confer cardioprotection through modulation of mitochondrial functions. We also investigated some potential PHD inhibitors as novel therapeutic agents in harnessing HIF-1’s cardioprotective effects. Methods/Results – Preinduction of HIF-1 was achieved by using tamoxifen-inducible cardiacspecific conditional VHL knockout mice in an acute manner as well as using a novel prolyl hydroxylase (PHD) inhibitor, GSK360A. In a separate study, another novel PHD inhibitor, FG- 6515 was administered post-infarction. Using the genetic approach, myocardial infarct size was lower in the VHL knockout mice compared to control groups. Cardiomyocytes isolated from these mice which were then subjected to simulated ischaemia-reperfusion injury (SIRI) also demonstrated increased cell survival although this effect was abolished with the inclusion of NSC-134754, a HIF-1 inhibitor. Pharmacological activation of HIF-1 conferred protection against ischemia in both isolated hearts as well as cardiomyocytes following SIRI. HIF-1 prevented generation excessive oxidative stress and decreased mitochondrial permeability transition pore (mPTP) sensitivity when measured in cardiomyocytes following an episode of SIRI. FG-6515 when administered post-infarction managed to reduce infarct size following 24 hours of recovery (reperfusion). Conclusions – Short term pre-induction of HIF-1 is beneficial. This study highlights the role of HIF-1 in maintaining the integrity of mitochondrial leading to enhanced cardioprotection. However, application of PHD inhibitors post-infarction is cardioprotective as well, indicating that pre-induction of HIF-1 although beneficial, is not an absolute must for increased survival