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 journalArticle

154 Citations (Scopus)

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 1 2012

Fingerprint

Purinergic P1 Receptors
Ischemia
Stabilization
Switches
Adenosine
Myocardial Ischemia
Period Circadian Proteins
Oxygen
Hypoxia-Inducible Factor 1
Ischemic Preconditioning
Enzyme Induction
Glycolysis
Circadian Rhythm
Metabolism
Carbohydrates
Availability
Light
Enzymes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Eckle, T., Hartmann, K., Bonney, S., Reithel, S., Mittelbronn, M., Walker, L. A., ... Eltzschig, H. K. (2012). Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia. Nature Medicine, 18(5), 774-782. https://doi.org/10.1038/nm.2728

Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia. / Eckle, Tobias; Hartmann, Katherine; Bonney, Stephanie; Reithel, Susan; Mittelbronn, Michel; Walker, Lori A.; Lowes, Brian D; Han, Jun; Borchers, Christoph H.; Buttrick, Peter M.; Kominsky, Douglas J.; Colgan, Sean P.; Eltzschig, Holger K.

In: Nature Medicine, Vol. 18, No. 5, 01.05.2012, p. 774-782.

Research output: Contribution to journalArticle

Eckle, T, Hartmann, K, Bonney, S, Reithel, S, Mittelbronn, M, Walker, LA, Lowes, BD, Han, J, Borchers, CH, Buttrick, PM, Kominsky, DJ, Colgan, SP & Eltzschig, HK 2012, 'Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia', Nature Medicine, vol. 18, no. 5, pp. 774-782. https://doi.org/10.1038/nm.2728
Eckle, Tobias ; Hartmann, Katherine ; Bonney, Stephanie ; Reithel, Susan ; Mittelbronn, Michel ; Walker, Lori A. ; Lowes, Brian D ; Han, Jun ; Borchers, Christoph H. ; Buttrick, Peter M. ; Kominsky, Douglas J. ; Colgan, Sean P. ; Eltzschig, Holger K. / Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia. In: Nature Medicine. 2012 ; Vol. 18, No. 5. pp. 774-782.
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