Lung oxidative stress and transcriptional regulations induced by estradiol and intermittent hypoxia

Abstract

We determined the effects of chronic intermittent hypoxia (CIH) and estradiol (E₂) on oxidative stress and gene expression in the lungs. Female Sprague-Dawley rats were left intact (sham) or ovariectomized (OVX) and implanted with pumps delivering vehicle or E₂ (0.5 mg/kg/day). Two weeks following surgery, the rats were exposed to room air (RA) or CIH for 7 days (10% O₂, 10 cycles/hour, 8 h/day). Lung samples were used to measure the activities of pro- (NADPH and xanthine oxidases) and antioxidant (superoxide dismutase, catalase and glutathione peroxidase) enzymes, and concentrations of advanced oxidation of protein products (AOPP). We determined gene expression with an RNA microarray and enrichment analysis of differentially expressed genes. In rats exposed to RA, OVX and E₂ supplementation increased pro- and antioxidant activities and AOPP concentration. In rats exposed to CIH, AOPP concentration, pro- and antioxidant enzymes activities increased in sham, did not changed in OVX-Veh rats, and were reduced in OVX-E₂ rats. In rats exposed to RA, genes involved in extracellular matrix were up-regulated by OVX and down-regulated by E₂, while E₂ up-regulated genes involved in cell mobility/adherence and leukocytes migration. OVX downregulated expression of roughly 200 olfactory receptor genes without effect of E₂. CIH altered gene expression in sham and OVX-E₂, but not in OVX-Veh rats. Enrichment analysis confirmed the antioxidant effects of E₂ under CIH. There are important interactions between ovarian hormones and CIH that can be relevant to better understand the consequences of sleep apnea (i.e. CIH) on the occurrence of lung pathologies in women.

Keywords: Female rats; Gene expression; Ovariectomy; Sex-hormones; Sleep apnea.