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

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.