Hypoxia-inducible factor-1 is central to cardioprotection: a new paradigm for ischemic preconditioning.
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.


RESULTS
Murine studies of in situ preconditioning revealed a robust activation of cardiac HIF-1. Moreover, in vivo small interfering RNA repression of cardiac HIF-1 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-1 alpha 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.


CONCLUSIONS
Taken together, these studies provide evidence for a critical role of HIF-1 in ischemic preconditioning via enhancing purinergic signaling pathways.
Eckle
Tobias
T
Department of Anesthesiology and Intensive Care Medicine, University Hospital, Tübingen, Germany.
Köhler
David
D
Lehmann
Rainer
R
El Kasmi
Karim
K
Eltzschig
Holger K
HK
D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000819:agonists / Q000502:physiology*; D019194:Ischemic Preconditioning; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000188:drug therapy; D011393:Procollagen-Proline Dioxygenase / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D043704:Receptor, Adenosine A2B / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction
D000600:Amino Acids, Dicarboxylic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D043704:Receptor, Adenosine A2B; D011393:Procollagen-Proline Dioxygenase; C040947:oxalylglycine