title: Metabolic homeostasis is maintained in myocardial hibernation by adaptive changes in the transcriptome and proteome.
abstract: A transgenic mouse model for conditional induction of long-term hibernation via myocardium-specific expression of a VEGF-sequestering soluble receptor allowed the dissection of the hibernation process into an initiation and a maintenance phase. The hypoxic initiation phase was characterized 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. Thus, we employed a combined "-omics" approach to resolve this cardioprotective adaptation process. Unguided bioinformatics analysis on the transcriptomic, proteomic and metabolomic 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. Although metabolite concentrations were kept relatively constant, the combination of the proteomic and transcriptomic dataset improved the statistical confidence of the pathway analysis by 2 orders of magnitude. Importantly, proteomics revealed a reduced phosphorylation state of myosin light chain 2 and cardiac troponin I within the contractile apparatus of hibernating hearts in the absence of changes in protein abundance. Our study demonstrates 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.
authors.affiliation: King's British Heart Foundation Centre, King's College London, London, UK. manuel.mayr@kcl.ac.uk
authors.forename: Manuel
authors.initials: M
authors.lastname: Mayr
authors.forename: Dalit
authors.initials: D
authors.lastname: May
authors.forename: Oren
authors.initials: O
authors.lastname: Gordon
authors.forename: Basetti
authors.initials: B
authors.lastname: Madhu
authors.forename: Dan
authors.initials: D
authors.lastname: Gilon
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Yin
authors.forename: Qiuru
authors.initials: Q
authors.lastname: Xing
authors.forename: Ignat
authors.initials: I
authors.lastname: Drozdov
authors.forename: Chrysanthi
authors.initials: C
authors.lastname: Ainali
authors.forename: Sophia
authors.initials: S
authors.lastname: Tsoka
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
authors.forename: John
authors.initials: J
authors.lastname: Griffiths
authors.forename: Anton
authors.initials: A
authors.lastname: Horrevoets
authors.forename: Eli
authors.initials: E
authors.lastname: Keshet
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D019295:Computational Biology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D053858:Metabolic Networks and Pathways / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D017682:Myocardial Stunning / Q000378:metabolism* / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000502:physiology; D020543:Proteome; D040901:Proteomics; D042442:Vascular Endothelial Growth Factors / Q000037:antagonists & inhibitors
chemical_list: D020543:Proteome; D042442:Vascular Endothelial Growth Factors