BAS/BSCR33 Cardioprotection by hypoxia-inducible factor-1 : underlying beneficial effects on mitochondrial function

Introduction Activation of hypoxia-inducible factor-1α (HIF-1α) protects the heart from ischaemia-reperfusion injury, although the underlying mechanisms are unclear. We hypothesised that HIF-1α-induced cardioprotection is mediated by beneficial effects on mitochondrial function. Methods and results Two different experimental models of HIF-1α activation were used: (1) pharmacological inhibition of proline hydroxylase (PHD) and (2) genetic inactivation of von Hippel-Lindau (VHL), proteins responsible for HIF-1α degradation under normoxic conditions. A single dose (3 mg/kg) of the PHD inhibitor (GSK0360A or PHDi), administered by oral gavage 4 h before ex vivo myocardial infarction, reduced myocardial infarct size (percentage of the area at risk) in male Sprague-Dawley rats (30.6%±2.9% PHDi vs 44.2%±2.9%; p5). Next, conditional cardiac-specific VHL knockout mice (VHL-KO) that express an inducible Cre-recombinase transgene to delete the VHL-floxed gene within the heart following tamoxifen induction, expressed higher levels of HIF-1 in the heart as assessed by immunostaining. The activation of myocardial HIF-1 resulted in a smaller myocardial infarct size in comparison with the littermate control (29.1%±4.7% in VHL-KO vs 52.5%±3.3% in control; p5/group). In VHL-KO cardiomyocytes subjected to simulated ischaemia-reperfusion injury (SIRI) (120 min ischaemia and 15 min reperfusion, the production of reactive oxygen species (ROS) (measured by reduced Mitotracker Red fluorescence)(1.0%±0.1-fold increase in VHL-KO vs 1.3%±0.2-fold increase in control; p3 experiments each with 40 cells) and mitochondrial permeability transition pore (mPTP) opening sensitivity was reduced (measured by TMRM fluorescence) (1.1%±0.1 fold increase in VHL-KO vs 1.4%±0.1 fold increase in control; p3 experiments each with 40 cells). Conclusions HIF-1α activation by genetic deletion of VHL or pharmacological inhibition of PHD, is cardioprotective and this protective effect can be attributed in part to beneficial effects on the mitochondria.