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.
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 mammalianoxygen 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.
Authors: Ming Cai; Zachary M Huttinger; Heng He; Weizhi Zhang; Feng Li; Lauren A Goodman; Debra G Wheeler; Lawrence J Druhan; Jay L Zweier; Karen M Dwyer; Guanglong He; Anthony J F d'Apice; Simon C Robson; Peter J Cowan; Richard J Gumina Journal: J Mol Cell Cardiol Date: 2011-09-12 Impact factor: 5.000
Authors: Marion Hölscher; Monique Silter; Sabine Krull; Melanie von Ahlen; Amke Hesse; Peter Schwartz; Ben Wielockx; Georg Breier; Dörthe M Katschinski; Anke Zieseniss Journal: J Biol Chem Date: 2011-01-26 Impact factor: 5.157
Authors: Hong Wei; Djahida Bedja; Norimichi Koitabashi; Dongmei Xing; Jasper Chen; Karen Fox-Talbot; Rosanne Rouf; Shaoping Chen; Charles Steenbergen; John W Harmon; Harry C Dietz; Kathleen L Gabrielson; David A Kass; Gregg L Semenza Journal: Proc Natl Acad Sci U S A Date: 2012-03-08 Impact factor: 11.205
Authors: Michael Tranter; Xiaoping Ren; Tiffany Forde; Michael E Wilhide; Jing Chen; Maureen A Sartor; Mario Medvedovic; W Keith Jones Journal: J Mol Cell Cardiol Date: 2010-07-16 Impact factor: 5.000