title: Proteomic Profiling Reveals Adaptive Responses to Surgical Myocardial Ischemia-Reperfusion in Hibernating Arctic Ground Squirrels Compared to Rats.
abstract: Hibernation is an adaptation to extreme environments known to provide organ protection against ischemia-reperfusion (I/R) injury. An unbiased systems approach was utilized to investigate hibernation-induced changes that are characteristic of the hibernator cardioprotective phenotype, by comparing the myocardial proteome of winter hibernating arctic ground squirrels (AGS), summer active AGS, and rats subjected to I/R, and further correlating with targeted metabolic changes.
  
  
  
  In a well-defined rodent model of I/R by deep hypothermic circulatory arrest followed by 3 or 24 h of reperfusion or sham, myocardial protein abundance in AGS (hibernating summer active) and rats (n = 4 to 5/group) was quantified by label-free proteomics (n = 4 to 5/group) and correlated with metabolic changes.
  
  
  
  Compared to rats, hibernating AGS displayed markedly reduced plasma levels of troponin I, myocardial apoptosis, and left ventricular contractile dysfunction. Of the 1,320 rat and 1,478 AGS proteins identified, 545 were differentially expressed between hibernating AGS and rat hearts (47% up-regulated and 53% down-regulated). Gene ontology analysis revealed down-regulation in hibernating AGS hearts of most proteins involved in mitochondrial energy transduction, including electron transport chain complexes, acetyl CoA biosynthesis, Krebs cycle, glycolysis, and ketogenesis. Conversely, fatty acid oxidation enzymes and sirtuin-3 were up-regulated in hibernating AGS, with preserved peroxisome proliferator-activated receptor-α activity and reduced tissue levels of acylcarnitines and ceramides after I/R.
  
  
  
  Natural cardioprotective adaptations in hibernators involve extensive metabolic remodeling, featuring increased expression of fatty acid metabolic proteins and reduced levels of toxic lipid metabolites. Robust up-regulation of sirtuin-3 suggests that posttranslational modifications may underlie organ protection in hibernating mammals.
authors.affiliation: From the Department of Anesthesiology, Duke University, Durham, North Carolina (Q.J.Q., Z.Z., Q.M., M.P.S., M.V.P.); Center for Genomic and Computational Biology - Proteomics Shared Resource, Duke University, Durham, North Carolina (E.S., M.A.M.); Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, North Carolina (J.B., C.B.N., M.J.M., M.H.); and Institute of Arctic Biology, University of Alaska, Fairbanks, Alaska (K.L.D., B.M.B., M.V.P.).
authors.forename: Quintin J
authors.initials: QJ
authors.lastname: Quinones
authors.forename: Zhiquan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Qing
authors.initials: Q
authors.lastname: Ma
authors.forename: Michael P
authors.initials: MP
authors.lastname: Smith
authors.forename: Erik
authors.initials: E
authors.lastname: Soderblom
authors.forename: M Arthur
authors.initials: MA
authors.lastname: Moseley
authors.forename: James
authors.initials: J
authors.lastname: Bain
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Muehlbauer
authors.forename: Matthew
authors.initials: M
authors.lastname: Hirschey
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Drew
authors.forename: Brian M
authors.initials: BM
authors.lastname: Barnes
authors.forename: Mihai V
authors.initials: MV
authors.lastname: Podgoreanu
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D005260:Female; D006605:Hibernation; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D040901:Proteomics; D051381:Rats; D020303:Rats, Inbred Dahl; D015427:Reperfusion Injury / Q000503:physiopathology*; D012589:Sciuridae