Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia

Tobias Eckle, Katherine Hartmann, Stephanie Bonney, Susan Reithel, Michel Mittelbronn, Lori A. Walker, Brian D. Lowes, Jun Han, Christoph H. Borchers, Peter M. Buttrick, Douglas J. Kominsky, Sean P. Colgan, Holger K. Eltzschig

Research output: Contribution to journalArticlepeer-review

179 Scopus citations

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-1Î ± (Hif-1Î ±). 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.

Original languageEnglish (US)
Pages (from-to)774-782
Number of pages9
JournalNature Medicine
Volume18
Issue number5
DOIs
StatePublished - May 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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