Transcriptional Regulations Induced by Estradiol and Intermittent Hypoxia in the Lungs of Ovariectomized Female Rats.

Intermittent hypoxia (IH) leads to oxidative stress and inflammation contributing to tissue and cellular dysfunctions in sleep apnea patients. We showed that estradiol (E2) reduces oxidative stress markers in the brain and aorta of female rats exposed to IH (model of sleep apnea), but it remains unknown if the effects of E2 in IH occur in other tissues such as the lungs, in which E2 receptors are present. Interestingly, both IH and E2 receptors act through specific transcription factors, changing the expression of target genes, and potential interactions between these transcription networks are not known. We therefore asked if IH exposure induces oxidative stress and alters the gene expression pattern in the lungs of ovariectomized female rats, and if E2 supplementation prevents these effects. Female Sprague‐Dawley rats were ovariectomized (OVX) and implanted with osmotic minipumps delivering vehicle (OVX‐VEH), or E2 (0.5 mg/kg/day). Two weeks following surgery, the rats were exposed to room air (RA), or IH for 7 days (nadir 10% O2, 10 cycles/hour, 8 hours/day). Lung samples were used to measure the oxidative stress marker AOPP (Advanced Oxidation of Protein Products) and determine the gene expression profiles (RNA microarray, ThermoFisher Clariom S rat assay). In OVX‐VEH female rats, E2 treatment, but not the IH exposure, increased AOPP level. In OVX‐Veh rats, IH upregulated the expression of 11 genes and down regulated 5 genes, none of these genes are involved in oxidative stress. E2 in RA rats upregulated 130 genes and downregulated 112 genes including CYP1a1, a cytochrome involved in production of reactive oxygen species. In rats treated with E2, the IH exposure increased the expression levels of 270 genes and decreased the expression of 828 genes (including anti‐oxidant genes). We conclude that in the lungs of OVX female rats, IH has only limited effects on oxidative stress and on genes transcriptional pattern. E2 treatment under RA conditions apparently increases oxidative stress and has more important transcriptional effects than IH exposure. Finally, E2 treatment has profound effects on the transcriptional response to IH exposure, and helps controlling the oxidative stress response. This important interaction between E2 and IH might be relevant to better understand the cellular responses to IH and sleep apnea in women.Support or Funding InformationSupported by CIHR.