Endogenous hydrogen sulfide contributes to uterine quiescence during pregnancy

Abstract

Recent evidence suggests that uterine activation for labor is associated with inflammation within uterine tissues. Hydrogen sulfide (H₂S) plays a critical role in inflammatory responses in various tissues. Our previous study has shown that human myometrium produces H₂S via its generating enzymes cystathionine-γ-lyase (CSE) and cystathionine-β-synthetase (CBS) during pregnancy. We therefore explored whether H₂S plays a role in the maintenance of uterine quiescence during pregnancy. Human myometrial biopsies were obtained from pregnant women at term. Uterine smooth muscle cells (UMSCs) isolated from myometrial tissues were treated with various reagents including H₂S. The protein expression of CSE, CBS and contraction-associated proteins (CAPs) including connexin 43, oxytocin receptor and prostaglandin F_2α receptor determined by Western blot. The levels of cytokines were measured by ELISA. The results showed that CSE and CBS expression inversely correlated to the levels of CAPs and activated NF-κB in pregnant myometrial tissues. H₂S inhibited the expression of CAPs, NF-κB activation and the production of interleukin (IL)-1β, IL-6 and tumor necrosis factor α (TNFα) in cultured USMCs. IL-1β treatment reversed H₂S inhibition of CAPs. Knockdown of CSE and CBS prevented H₂S suppression of inflammation. H₂S modulation of inflammation is through K_ATP channels and phosphoinositide 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) signaling pathways. H₂S activation of PI3K and ERK signaling is dependent on K_ATP channels. Our data suggest that H₂S suppresses the expression of CAPs via inhibition of inflammation in myometrium. Endogenous H₂S is one of the key factors in maintenance of uterine quiescence during pregnancy.