Abstract 1810: Metabolic Homeostasis is Maintained in Myocardial Hibernation by Adaptive Changes in the Transcriptome and Proteome
Background: Hibernation is a cardioprotective response that preserves myocardial viability under hypoxia. 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 dissect mechanisms of cardiac adaptation by integrating mRNA, protein and metabolite changes.
Methods and Results: A mouse genome array, difference in-gel electrophoresis, and proton nuclear magnetic resonance spectroscopy were employed to analyse the transcriptome, proteome and metabolome of control and hibernating hearts, respectively. Despite an overall correlation between mRNA and protein expression, alterations in post-translational modifications, such as phosphorylation of myofilament proteins and redox-modifications, accounted for discrepancies between the transcriptomic and the proteomic data. 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. Strikingly, the combination of the proteomic and transcriptomic dataset improved the statistical confidence of the pathway analysis by 2 orders of magnitude, with HIF-Hypoxia-Akt signaling and glycolysis being the most significant. In addition, the combined data pointed towards the activation of hydroxyproline production, a pivotal component of collagen synthesis. The metabolite data did not add to the pathway analysis as the corresponding metabolite concentrations were kept relatively constant, although taurine, lactate, and creatine levels did account for most of the discrimination between hibernating and control hearts in a principal component analysis.
Conclusion: 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 homeostasis is likely to contribute to the long-term survival of the hibernating myocardium.