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.