7β-estradiol protects esophageal epithelial injury against noxious refluxes-induced oxidative stress via SIRT3-MnSOD signaling

Abstract Estrogen and oxidative stress are associated with reflux esophagitis (RE) and its underlying complications. It has been reported that 17β-estradiol (E2) protects the esophageal mucosa via its antioxidant properties. Sirtuin-3 (SIRT3) is a member of the Sirtuin family that protects against diseases related to oxidative stress. We hypothesized that E2 protects against esophageal epithelial injury induced by noxious refluxes by activating the SIRT3 signaling pathway. In human esophageal epithelial cells (Het-1A), acidic bile salts (BA/A) at a 200 µM concentration damaged the cell barrier function, which was mediated by reactive oxygen species (ROS). However, E2 (200 nM) treatment reversed these findings. BA/A-induced ROS originated from mitochondria and NADPH oxidases, with mitochondrial ROS having a more significant impairing effect on cell barrier function. E2 treatment upregulated SIRT3 expression and activity, subsequently leading to manganese superoxide dismutase (MnSOD) deacetylation and ROS downregulation under BA/A conditions. Moreover, the protective role of E2 was abolished by the inhibition of SIRT3. In addition, E2 upregulated SIRT3 expression via ERβ. Rats were successfully subjected to an esophagoduodenostomy operation and subsequently treated with or without E2 ex vitro. The results showed an increased SIRT3 expression, decreased MnSOD acetylation, and upregulated ERβ expression. Our research demonstrates that E2 treatment protects against esophageal epithelial injury by reducing BA/A-induced oxidative stress by activating the ERβ-SIRT3-MnSOD signaling pathway.