Background— Ischemic preconditioning provides strong cardioprotection from ischemia, but its molecular mechanisms remain unknown. Convincing evidence confirms a central role of hypoxia-inducible factor (HIF)-1 in mammalian oxygen homeostasis. Thus, we pursued HIF-1 as a central component of cardioprotection by ischemic preconditioning.

Methods and Results— Murine studies of in situ preconditioning revealed a robust activation of cardiac HIF-1α. Moreover, in vivo small interfering RNA repression of cardiac HIF-1α resulted in abolished cardioprotection by ischemic preconditioning. In contrast, pretreatment with the HIF activator dimethyloxalylglycine was associated with cardioprotection similar to that of ischemic preconditioning itself. Finally, selective small interfering RNA repression of prolylhydroxylase 2 resulted in significant activation of HIF-1α and attenuated myocardial infarct sizes (0.44±0.09-fold). As an end point of HIF-dependent cardioprotection, we defined the role of A2B adenosine receptor (A2BAR) signaling. Although the cardiac A2BAR was induced with HIF activation, HIF-dependent cardioprotection was abolished in A2BAR^−/− mice.

Conclusion— Taken together, these studies provide evidence for a critical role of HIF-1 in ischemic preconditioning via enhancing purinergic signaling pathways.