期刊
NATURE MEDICINE
卷 18, 期 5, 页码 774-U173出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2728
关键词
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资金
- National Heart, Lung and Blood Institute [R01-HL092188, R01-DK083385, R01-HL098294, R01-HL060569, 1K08HL102267]
- Foundation for Anesthesia Education and Research
- American Heart Association
- Crohn's and Colitis Foundation of America
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.
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