Delayed myocardial preconditioning induced by cobalt chloride in the rat: HIF-1α and iNOS involvement

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)-1a, 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 (CoCl2) is known to promote HIF-1a stabilization by inhibiting prolyl hydroxylase activity, we hypothesized that CoCl2 could mimic the cardioprotective effects of hypoxia. Two groups of rats were administered 30 mg/kg twice of CoCl2 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 mu m, prior to ischemia). The role of HIF-1a was investigated by preventing its stabilization using cadmium chloride (CdCl2, 1 mg/kg), administered 1 h before cobalt treatment. Treatment by CoCl2 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. CdCl2 pretreatment and Ag perfusion abolished the beneficial effects on both infarct size and CF. Thus, the hypoxia-sensitive transcription factor HIF-1a 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.