title: Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia.
abstract: Adenosine signaling has been implicated in cardiac adaptation to limited oxygen availability. In a wide search for adenosine receptor A2b (Adora2b)-elicited cardioadaptive responses, we identified the circadian rhythm protein period 2 (Per2) as an Adora2b target. Adora2b signaling led to Per2 stabilization during myocardial ischemia, and in this setting, Per2(-/-) mice had larger infarct sizes compared to wild-type mice and loss of the cardioprotection conferred by ischemic preconditioning. Metabolic studies uncovered a limited ability of ischemic hearts in Per2(-/-) mice to use carbohydrates for oxygen-efficient glycolysis. This impairment was caused by a failure to stabilize hypoxia-inducible factor-1α (Hif-1α). Moreover, stabilization of Per2 in the heart by exposing mice to intense light resulted in the transcriptional induction of glycolytic enzymes and Per2-dependent cardioprotection from ischemia. Together, these studies identify adenosine-elicited stabilization of Per2 in the control of HIF-dependent cardiac metabolism and ischemia tolerance and implicate Per2 stabilization as a potential new strategy for treating myocardial ischemia.
authors.affiliation: Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado Denver, Aurora, USA. tobias.eckle@ucdenver.edu
authors.forename: Tobias
authors.initials: T
authors.lastname: Eckle
authors.forename: Katherine
authors.initials: K
authors.lastname: Hartmann
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bonney
authors.forename: Susan
authors.initials: S
authors.lastname: Reithel
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Lori A
authors.initials: LA
authors.lastname: Walker
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lowes
authors.forename: Jun
authors.initials: J
authors.lastname: Han
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Borchers
authors.forename: Peter M
authors.initials: PM
authors.lastname: Buttrick
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Kominsky
authors.forename: Sean P
authors.initials: SP
authors.lastname: Colgan
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D002478:Cells, Cultured; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D056950:Period Circadian Proteins / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000502:physiology*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C421902:PER2 protein, human; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D043704:Receptor, Adenosine A2B; D046988:Proteasome Endopeptidase Complex