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

doi:10.1038/nm.2728

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

287 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 language	English
Pages (from-to)	774-782
Number of pages	9
Journal	Nature Medicine
Volume	18
Issue number	5
DOIs	https://doi.org/10.1038/nm.2728
Publication status	Published - May 2012
Externally published	Yes

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Eckle, T., Hartmann, K., Bonney, S., Reithel, S., Mittelbronn, M., Walker, L. A., Lowes, B. D., Han, J., Borchers, C. H., Buttrick, P. M., Kominsky, D. J., Colgan, S. P., & 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

@article{de669d556b22464d8de125871c8d839d,

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-1{\^I} ± (Hif-1{\^I} ±). 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.",

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

note = "Funding Information: The authors acknowledge S.A. Eltzschig (Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado, USA) for artwork during manuscript preparation, A. Medway (Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA), K. Hoffmann, J. Macas and C. Zachskorn (Institute of Neurology (Edinger Institute), University of Frankfurt, Frankfurt, Germany) and M. Bonney (Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado, USA) for technical assistance and C.-C. Lee (Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, Texas, USA) for providing the Per1−/− mice. The present research work is supported by National Heart, Lung and Blood Institute grants R01-HL092188, R01-DK083385 and R01-HL098294 to H.K.E., R01-HL060569 to S.P.C. and 1K08HL102267 to T.E., Foundation for Anesthesia Education and Research grants to T.E. and H.K.E., an American Heart Association grant to T.E. and a Crohn{\textquoteright}s and Colitis Foundation of America grant to H.K.E.",

year = "2012",

month = may,

doi = "10.1038/nm.2728",

language = "English",

volume = "18",

pages = "774--782",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Research",

number = "5",

}

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

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.

N1 - Funding Information: The authors acknowledge S.A. Eltzschig (Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado, USA) for artwork during manuscript preparation, A. Medway (Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA), K. Hoffmann, J. Macas and C. Zachskorn (Institute of Neurology (Edinger Institute), University of Frankfurt, Frankfurt, Germany) and M. Bonney (Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado, USA) for technical assistance and C.-C. Lee (Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, Texas, USA) for providing the Per1−/− mice. The present research work is supported by National Heart, Lung and Blood Institute grants R01-HL092188, R01-DK083385 and R01-HL098294 to H.K.E., R01-HL060569 to S.P.C. and 1K08HL102267 to T.E., Foundation for Anesthesia Education and Research grants to T.E. and H.K.E., an American Heart Association grant to T.E. and a Crohn’s and Colitis Foundation of America grant to H.K.E.

PY - 2012/5

Y1 - 2012/5

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.

UR - https://www.scopus.com/pages/publications/84860663922

U2 - 10.1038/nm.2728

DO - 10.1038/nm.2728

M3 - Article

C2 - 22504483

AN - SCOPUS:84860663922

SN - 1078-8956

VL - 18

SP - 774

EP - 782

JO - Nature Medicine

JF - Nature Medicine

IS - 5

ER -

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

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