Induction of inducible nitric oxide synthase by isoflurane post-conditioning via hypoxia inducible factor-1α during tolerance against ischemic neuronal injury

Recent studies have shown that isoflurane protects against ischemic injury via inducible nitric oxide synthase (iNOS). Hypoxia inducible factor (HIF)-1α is a transcriptional factor that activates after cerebral ischemia. However, whether iNOS gene containing the sequence of the hypoxia response element (HRE) is a HIF-1α target during tolerance against ischemic neuronal injury induced by isoflurane post-conditioning remains unknown. In this study, we report that HIF-1α and iNOS gene expression were augmented after cerebral ischemia in rats. Furthermore, isoflurane post-conditioning resulted in greater accumulation of HIF-1α and iNOS gene expression, following by HIF-1α transcriptional activity enhancement and co-localization of HIF-1α and iNOS. Accordingly, in the primary cortical neuron cultures, silencing of HIF-1α attenuated the accumulation of iNOS and the protective effects of isoflurane post-conditioning. Our results suggest the involvement of HIF-1α in the regulation of iNOS during tolerance against cerebral ischemia induced by isoflurane post-conditioning, which provide a mechanistic basis of novel therapeutic strategies for ischemic stroke.

► Isoflurane post-conditioning induced neuronal ischemic tolerance in vivo and in vitro. ► Neuronal ischemia in vivo and in vitro induced HIF-1α and iNOS gene expression. ► Knockdown of HIF-1α attenuated the protection and accumulation of iNOS induced by isoflurane post-conditioning.