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 language | English (US) |
|---|---|
| Pages (from-to) | 774-782 |
| Number of pages | 9 |
| Journal | Nature Medicine |
| Volume | 18 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2012 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
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 journal › Article
}
TY - JOUR
T1 - Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia
AU - Eckle, Tobias
AU - Hartmann, Katherine
AU - Bonney, Stephanie
AU - Reithel, Susan
AU - Mittelbronn, Michel
AU - Walker, Lori A.
AU - Lowes, Brian D
AU - Han, Jun
AU - Borchers, Christoph H.
AU - Buttrick, Peter M.
AU - Kominsky, Douglas J.
AU - Colgan, Sean P.
AU - Eltzschig, Holger K.
PY - 2012/5/1
Y1 - 2012/5/1
N2 - 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.
AB - 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.
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U2 - 10.1038/nm.2728
DO - 10.1038/nm.2728
M3 - Article
VL - 18
SP - 774
EP - 782
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 5
ER -