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Delayed myocardial preconditioning induced by cobalt chloride in the rat: HIF-1α and iNOS involvement.
MedLine Citation:
PMID:  21480981     Owner:  NLM     Status:  Publisher    
We previously reported that acute exposure to intermittent hypoxia results in delayed cardioprotection against ischemia/reperfusion (I/R) injury and that the hypoxia-inducible factor (HIF)-1α, a transcriptional factor stabilized by hypoxia, as well as inducible nitric oxide synthase (iNOS) play a key role in this form of preconditioning. As cobalt chloride (CoCl(2) ) is known to promote HIF-1α stabilization by inhibiting prolyl hydroxylase activity, we hypothesized that CoCl(2) could mimic the cardioprotective effects of hypoxia. Two groups of rats were administered 30 mg/kg twice of CoCl(2) or sterile water. Twenty-four hours later, hearts were perfused in Langendorff mode and subjected to an I/R protocol. Infarct size and functional recovery were studied. The role of iNOS was assessed by measuring myocardial iNOS content and by observing the effects of the iNOS inhibitor aminoguanidine (Ag, 100 μm, prior to ischemia). The role of HIF-1α was investigated by preventing its stabilization using cadmium chloride (CdCl(2) , 1 mg/kg), administered 1 h before cobalt treatment. Treatment by CoCl(2) significantly reduced myocardial infarction by 33% and increased coronary flow (CF) at reperfusion by 27% compared with control rats, and this was accompanied by a threefold increase in myocardial iNOS content. CdCl(2) pretreatment and Ag perfusion abolished the beneficial effects on both infarct size and CF. Thus, the hypoxia-sensitive transcription factor HIF-1α and iNOS appear to play a pivotal role in the delayed pharmacological myocardial preconditioning induced by cobalt, thus mimicking the effects of hypoxic preconditioning. These results underscore the importance of prolyl hydroxylases as potential therapeutic targets for cardioprotection.
Elise Belaidi; Pauline C Beguin; Patrick Levy; Christophe Ribuot; Diane Godin-Ribuot
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-4-11
Journal Detail:
Title:  Fundamental & clinical pharmacology     Volume:  -     ISSN:  1472-8206     ISO Abbreviation:  -     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-4-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8710411     Medline TA:  Fundam Clin Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2011 The Authors Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique.
Laboratoire HP2, Hypoxie et Physiopathologies Cardiovasculaire et Respiratoire, INSERM U 1042, Grenoble, F-38042 France Université Grenoble 1, Faculté de Médecine, EA-3745, IFR1, Grenoble, F-38042 France CHU, Hôpital A. Michallon, Laboratoire EFCR, BP217X, Grenoble, F-38043 France.
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