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

Nat Med. 2012 Apr 15;18(5):774-82. doi: 10.1038/nm.2728.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Animals
  • Cells, Cultured
  • Glycolysis
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Ischemia / metabolism*
  • Myocardium / metabolism*
  • Period Circadian Proteins / physiology*
  • Proteasome Endopeptidase Complex / metabolism
  • Receptor, Adenosine A2B / physiology*


  • Hypoxia-Inducible Factor 1, alpha Subunit
  • PER2 protein, human
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Receptor, Adenosine A2B
  • Proteasome Endopeptidase Complex