Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia.
Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia.
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作者：
环境应激中代谢适应的研究在人类疾病中有着广泛的应用。腺苷信号转导与心脏对有限的氧气供应的适应有关。偶然的是，对腺苷受体A2B(Adora2b)引起的心脏适应性反应的广泛搜索发现了昼夜节律蛋白Perod2(PER2)。随后的药理学和遗传学研究证实，心肌缺血期间PER2的稳定依赖于Adora2b。对PER2−/−小鼠心肌缺血的功能研究显示，心肌梗死面积较大，并取消了缺血预适应的心脏保护作用。心肌缺血期间的代谢研究发现，PER2−/−小鼠通过氧高效糖酵解利用碳水化合物的能力有限。这些代谢变化与PER2−/−小鼠未能稳定低氧诱导因子HIF1a有关。此外，PER2通过光暴露转录增强糖酵解来稳定心脏，并提供针对缺血的特定时期的心脏保护。总之，这些研究确认PER2是通过心脏代谢的重新编程而调节缺血耐受性的关键因素，并暗示PER2是急性心肌缺血的新的治疗方式。
Studies of metabolic adaptation during environmental stress have broad applications to human disease. Adenosine signaling has been implicated in cardiac adaptation to limited oxygen availability. Serendipitously, a wide search for adenosine receptor A2b (Adora2b)-elicited cardio-adaptive responses identified the circadian rhythm protein period2 (Per2). Subsequent pharmacologic and genetic studies confirmed Adora2b-dependent stabilization of Per2 during myocardial ischemia. Functional studies of myocardial ischemia in Per2−/− mice revealed larger infarct sizes and abolished cardio-protection by ischemic preconditioning. Metabolic studies during myocardial ischemia uncovered a limited ability of Per2−/− mice to utilize carbohydrates via oxygen-efficient glycolysis. These metabolic alterations were associated with a failure in Per2−/− mice to stabilize hypoxia-inducible-factor Hif1a. Moreover, cardiac stabilization of Per2 via light-exposure transcriptionally enhanced glycolysis, and provided period-specific cardio-protection from ischemia. Together, these studies identify Per2 as key regulator of ischemia tolerance through reprogramming of cardiac metabolism and implicate Per2 as novel therapeutic modality during acute myocardial ischemia.
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影响因子：
20.1
作者：
Durgan DJ;Pulinilkunnil T;Villegas-Montoya C;Garvey ME;Frangogiannis NG;Michael LH;Chow CW;Dyck JR;Young ME
通讯作者：
Young ME
影响因子：
2.8
作者：
Leibetseder, Valentin;Humpeler, Susanne;Ekmekcioglu, Cem
通讯作者：
Ekmekcioglu, Cem
影响因子：
4.8
作者：
Daniels, Isadora Susan;Zhang, Jianfa;Lee, Cheng Chi
通讯作者：
Lee, Cheng Chi
DOI：
10.1152/ajpheart.00472.2006
发表时间：
2006-11-01
影响因子：
4.8
作者：
Eckle, Tobias;Grenz, Almut;Eltzschig, Holger K.
通讯作者：
Eltzschig, Holger K.
影响因子：
15.9
作者：
Khoury, Joseph;Ibla, Juan C.;Colgan, Sean R.
通讯作者：
Colgan, Sean R.