Document Detail

Hypoxia-inducible factor-1 is central to cardioprotection: a new paradigm for ischemic preconditioning.
MedLine Citation:
PMID:  18591435     Owner:  NLM     Status:  MEDLINE    
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-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. CONCLUSION: Taken together, these studies provide evidence for a critical role of HIF-1 in ischemic preconditioning via enhancing purinergic signaling pathways.
Tobias Eckle; David Köhler; Rainer Lehmann; Karim El Kasmi; Holger K Eltzschig
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Circulation     Volume:  118     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2008 Jul 
Date Detail:
Created Date:  2008-07-10     Completed Date:  2008-07-23     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  166-75     Citation Subset:  AIM; IM    
Department of Anesthesiology and Intensive Care Medicine, University Hospital, Tübingen, Germany.
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MeSH Terms
Amino Acids, Dicarboxylic / pharmacology
Hypoxia-Inducible Factor 1, alpha Subunit / agonists,  physiology*
Ischemic Preconditioning*
Mice, Knockout
Myocardial Infarction / drug therapy
Procollagen-Proline Dioxygenase / drug effects
RNA, Small Interfering / pharmacology
Receptor, Adenosine A2B / deficiency,  physiology*
Signal Transduction
Reg. No./Substance:
0/Amino Acids, Dicarboxylic; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/RNA, Small Interfering; 0/Receptor, Adenosine A2B; 5262-39-5/oxalylglycine; EC Dioxygenase

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