Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado Denver, Aurora, USA.
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.
腺苷信号在心脏适应有限氧气供应中起作用。在广泛寻找腺苷受体 A2b（Adora2b）引起的心脏适应性反应的过程中，我们发现昼夜节律蛋白周期 2（Per2）是 Adora2b 的靶标。Adora2b 信号导致心肌缺血期间 Per2 的稳定，在这种情况下，与野生型小鼠相比，Per2（-/-）小鼠的梗死面积更大，并且失去了缺血预处理赋予的心脏保护作用。代谢研究揭示了 Per2（-/-）小鼠缺血心脏利用碳水化合物进行高效糖酵解的能力有限。这种损伤是由于不能稳定缺氧诱导因子-1α（Hif-1α）造成的。此外，通过让小鼠暴露在强光下稳定心脏中的 Per2，导致糖酵解酶的转录诱导以及 Per2 依赖性对缺血的心脏保护作用。总之，这些研究确定了腺苷诱导的 Per2 稳定在控制 HIF 依赖的心脏代谢和缺血耐受中的作用，并暗示 Per2 稳定可能是治疗心肌缺血的一种新策略。
