Phosphorylation of phosphatidylinositol-3-kinase-protein kinase B and extracellular signal-regulated kinases 1/2 mediate reoxygenation-induced cardioprotection during hypoxia.

Détails

ID Serval
serval:BIB_FAACF39E287C
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Phosphorylation of phosphatidylinositol-3-kinase-protein kinase B and extracellular signal-regulated kinases 1/2 mediate reoxygenation-induced cardioprotection during hypoxia.
Périodique
Experimental Biology and Medicine
Auteur(s)
Milano G., von Segesser L.K., Morel S., Joncic A., Bianciardi P., Vassalli G., Samaja M.
ISSN
1535-3699[electronic], 1535-3699[linking]
Statut éditorial
Publié
Date de publication
2010
Volume
235
Numéro
3
Pages
401-410
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Résumé
In vivo exposure to chronic hypoxia (CH) depresses myocardial performance and tolerance to ischemia, but daily reoxyenation during CH (CHR) confers cardioprotection. To elucidate the underlying mechanism, we tested the role of phosphatidylinositol-3-kinase-protein kinase B (Akt) and p42/p44 extracellular signal-regulated kinases (ERK1/2), which are known to be associated with protection against ischemia/reperfusion (I/R). Male Sprague-Dawley rats were maintained for two weeks under CH (10% O(2)) or CHR (as CH but with one-hour daily exposure to room air). Then, hearts were either frozen for biochemical analyses or Langendorff-perfused to determine performance (intraventricular balloon) and tolerance to 30-min global ischemia and 45-min reperfusion, assessed as recovery of performance after I/R and infarct size (tetrazolium staining). Additional hearts were perfused in the presence of 15 micromol/L LY-294002 (inhibitor of Akt), 10 micromol/L UO-126 (inhibitor of ERK1/2) or 10 micromol/L PD-98059 (less-specific inhibitor of ERK1/2) given 15 min before ischemia and throughout the first 20 min of reperfusion. Whereas total Akt and ERK1/2 were unaffected by CH and CHR in vivo, in CHR hearts the phosphorylation of both proteins was higher than in CH hearts. This was accompanied by better performance after I/R (heart rate x developed pressure), lower end-diastolic pressure and reduced infarct size. Whereas the treatment with LY-294002 decreased the phosphorylation of Akt only, the treatment with UO-126 decreased ERK1/2, and that with PD-98059 decreased both Akt and ERK1/2. In all cases, the cardioprotective effect led by CHR was lost. In conclusion, in vivo daily reoxygenation during CH enhances Akt and ERK1/2 signaling. This response was accompanied by a complex phenotype consisting in improved resistance to stress, better myocardial performance and lower infarct size after I/R. Selective inhibition of Akt and ERK1/2 phosphorylation abolishes the beneficial effects of the reoxygenation. Therefore, Akt and ERK1/2 have an important role to mediate cardioprotection by reoxygenation during CH in vivo.
Mots-clé
1-Phosphatidylinositol 3-Kinase/metabolism, Animals, Anoxia/pathology, Chromones/pharmacology, Enzyme Inhibitors/pharmacology, Extracellular Signal-Regulated MAP Kinases/metabolism, Flavonoids/pharmacology, Male, Morpholines/pharmacology, Oxygen/metabolism, Perfusion, Phosphorylation, Proto-Oncogene Proteins c-akt/metabolism, Rats, Rats, Sprague-Dawley, Reperfusion Injury
Pubmed
Web of science
Création de la notice
28/06/2010 18:13
Dernière modification de la notice
03/03/2018 22:56
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