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Up-regulation of Hypoxia Inducible Factor 1α by Isoflurane in Hep3B Cells

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Abstract

Background:

The volatile anesthetic isoflurane induces hypoxia inducible factor (HIF)-1–responsive genes heme oxygenase 1, inducible nitric oxide synthase, and vascular endothelial growth factor (VEGF) expression. Little is known about the extent to which induction of HIF-1α is affected by isoflurane.

Methods:

Hep3B cells were exposed to isoflurane at various concentrations (0.5–4%) or for different time periods (2–8 h) at 37°C. HIF-1α gene expression and transcriptional activity, heme oxygenase 1, inducible nitric oxide synthase, and VEGF gene expression were quantified.

Results:

Isoflurane induced a time- and concentration-dependent increase in HIF-1α protein but not for HIF-1α messenger RNA (mRNA) in Hep3B cells. The maximal increase was induced by 2% isoflurane, and the cells incubated with 2% isoflurane for 4–8 h expressed the highest protein. Similarly, HIF-1α transcriptional activity was higher in Hep3B cells exposed to 2% isoflurane for 16 h than that in control cells. The combination of 2% isoflurane and desferrioxamine, a hypoxia mimetic, caused a higher level of HIF-1α protein than that induced by 2% isoflurane alone. Reoxygenation and inhibitor of proteasome pathway MG132 did not affect the isoflurane-induced HIF-1α protein accumulation. Cycloheximide, an inhibitor for protein synthesis, completely abrogated the induction of HIF-1α protein by isoflurane. Isoflurane stimulated heme oxygenase 1, inducible nitric oxide synthase, and VEGF mRNA expression in a concentration-dependent manner, and inactivation of HIF-1α attenuated the induction of VEGF mRNA by isoflurane.

Conclusion:

Isoflurane can up-regulate HIF-1α and enhance HIF-1–responsive genes heme oxygenase 1, inducible nitric oxide synthase, and VEGF mRNA expression in Hep3B cells. The induction of HIF-1α by isoflurane does not involve protein degradation but depends on translation pathway.

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