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

被引:266
作者
Eckle, Tobias [1 ]
Hartmann, Katherine [1 ]
Bonney, Stephanie [1 ]
Reithel, Susan [1 ]
Mittelbronn, Michel [2 ]
Walker, Lori A. [3 ]
Lowes, Brian D. [3 ]
Han, Jun [4 ]
Borchers, Christoph H. [4 ]
Buttrick, Peter M. [3 ]
Kominsky, Douglas J. [1 ]
Colgan, Sean P. [5 ]
Eltzschig, Holger K. [1 ]
机构
[1] Univ Colorado Denver, Dept Anesthesiol, Mucosal Inflammat Program, Aurora, CO USA
[2] Goethe Univ Frankfurt, Edinger Inst, Inst Neurol, Frankfurt, Germany
[3] Univ Colorado Denver, Div Cardiol, Dept Med, Aurora, CO USA
[4] Univ Victoria, Dept Biochem & Microbiol, Genome BC Prote Ctr, Victoria, BC, Canada
[5] Univ Colorado Denver, Dept Med, Mucosal Inflammat Program, Aurora, CO USA
关键词
CIRCADIAN CLOCK; GLUCOSE-METABOLISM; TISSUE-DAMAGE; INFARCT SIZE; MOUSE MODEL; ADENOSINE; HYPOXIA; REPERFUSION; MECHANISMS; EXPRESSION;
D O I
10.1038/nm.2728
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 alpha (Hif-1 alpha). 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.
引用
收藏
页码:774 / U173
页数:11
相关论文
共 60 条
[11]   Cardioprotection by ecto-5′-nucleotidase (CD73) and A2B adenosine receptors [J].
Eckle, Tobias ;
Krahn, Thomas ;
Grenz, Almut ;
Koehler, David ;
Mittelbronn, Michel ;
Ledent, Catherine ;
Jacobson, Marlene A. ;
Osswald, Hartmut ;
Thompson, Linda F. ;
Unertl, Klaus ;
Eltzschig, Holger K. .
CIRCULATION, 2007, 115 (12) :1581-1590
[12]   Systematic evaluation of a novel model for cardiac ischemic preconditioning in mice [J].
Eckle, Tobias ;
Grenz, Almut ;
Koehler, David ;
Redel, Andreas ;
Falk, Melanie ;
Rolauffs, Bernd ;
Osswald, Hartmut ;
Kehl, Franz ;
Eltzschig, Holger K. .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2006, 291 (05) :H2533-H2540
[13]   Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium:: Role of ectonucleotidases and adenosine A2B receptors [J].
Eltzschig, HK ;
Ibla, JC ;
Furuta, GT ;
Leonard, MO ;
Jacobson, KA ;
Enjyoji, K ;
Robson, SC ;
Colgan, SP .
JOURNAL OF EXPERIMENTAL MEDICINE, 2003, 198 (05) :783-796
[14]   Ischemia and reperfusion-from mechanism to translation [J].
Eltzschig, Holger K. ;
Eckle, Tobias .
NATURE MEDICINE, 2011, 17 (11) :1391-1401
[15]   Mechanisms of Disease: Hypoxia and Inflammation. [J].
Eltzschig, Holger K. ;
Carmeliet, Peter .
NEW ENGLAND JOURNAL OF MEDICINE, 2011, 364 (07) :656-665
[16]   ADENOSINE ALTERS GLUCOSE USE DURING ISCHEMIA AND REPERFUSION IN ISOLATED RAT HEARTS [J].
FINEGAN, BA ;
LOPASCHUK, GD ;
COULSON, CS ;
CLANACHAN, AS .
CIRCULATION, 1993, 87 (03) :900-908
[17]   Adenosine, an endogenous distress signal, modulates tissue damage and repair [J].
Fredholm, B. B. .
CELL DEATH AND DIFFERENTIATION, 2007, 14 (07) :1315-1323
[18]   Post-translational modifications regulate the ticking of the circadian clock [J].
Gallego, Monica ;
Virshup, David M. .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2007, 8 (02) :139-148
[19]   REGULATION OF CREB PHOSPHORYLATION IN THE SUPRACHIASMATIC NUCLEUS BY LIGHT AND A CIRCADIAN CLOCK [J].
GINTY, DD ;
KORNHAUSER, JM ;
THOMPSON, MA ;
BADING, H ;
MAYO, KE ;
TAKAHASHI, JS ;
GREENBERG, ME .
SCIENCE, 1993, 260 (5105) :238-241
[20]   PER2 Controls Lipid Metabolism by Direct Regulation of PPARγ [J].
Grimaldi, Benedetto ;
Bellet, Marina Maria ;
Katada, Sayako ;
Astarita, Giuseppe ;
Hirayama, Jun ;
Amin, Rajesh H. ;
Granneman, James G. ;
Piomelli, Daniele ;
Leff, Todd ;
Sassone-Corsi, Paolo .
CELL METABOLISM, 2010, 12 (05) :509-520