Rationale We have recently established a transgenic mouse model for conditional induction of long-term hibernation via myocardium-specific induction of a VEGF-sequestering soluble receptor.
Objective Using a combined ‘-omics’ approach, we aim to resolve the cardioprotective response that preserves myocardial viability under chronic hypoxia by integrating mRNA, protein and metabolite changes in unsupervised network analysis.
Methods and results A genome array, difference in gel electrophoresis and proton nuclear magnetic resonance spectroscopy were employed to dissect the hibernation process into an initiation and a maintenance phase. The initiation phase was characterised by peak levels of K(ATP) channel and glucose transporter 1 (GLUT1) expression. Glibenclamide, an inhibitor of K(ATP) channels, blocked GLUT1 induction. In the maintenance phase, tissue hypoxia and GLUT1 expression were reduced and metabolite concentrations were kept relatively constant. Unguided bioinformatics analysis on the combined datasets confirmed that anaerobic glycolysis was affected and that the observed enzymatic changes in cardiac metabolism were directly linked to hypoxia-inducible factor (HIF)-1 activation. Notably, the combination of the proteomic and transcriptomic datasets improved the statistical confidence of the pathway analysis by two orders of magnitude, with HIF–hypoxia–Akt signalling and glycolysis being the most significant.
Conclusions We demonstrate how combining different ‘-omics’ datasets aids in the identification of key biological pathways: chronic hypoxia resulted in a pronounced adaptive response at the transcript and the protein level to keep metabolite levels steady. This preservation of metabolic homoeostasis is likely to contribute to the long-term survival of the hibernating myocardium.
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