Expression of Cystathionine β-synthase and Cystathionine γ-lyase in Human Pregnant Myometrium and Their Roles in the Control of Uterine Contractility

Abstract

BackgroundHuman uterus undergoes distinct molecular and functional changes during pregnancy and parturition. Hydrogen sulfide (H2S) has recently been shown to play a key role in the control of smooth muscle tension. The role of endogenous H2S produced locally in the control of uterine contractility during labour is unknown.Methodology/Principal FindingsHuman myometrium biopsies were obtained from pregnant women undergoing cesarean section at term. Immunohistochemistry analysis showed that cystathionine-γ-lyase (CSE) and cystathionine-β-synthetase (CBS), the principle enzymes responsible for H2S generation, were mainly localized to smooth muscle cells of human pregnant myometrium. The mRNA and protein expression of CBS as well as H2S production rate were down-regulated in labouring tissues compared to nonlabouring tissues. Cumulative administration of L-cysteine (10−7–10−2 mol/L), a precursor of H2S, caused a dose-dependent decrease in the amplitude of spontaneous contractions in nonlabouring and labouring myometrium strips. L-cysteine at high concentration (10−3 mol/L) increased the frequency of spontaneous contractions and induced tonic contraction. These effects of L-cysteine were blocked by the inhibitors of CBS and CSE. Pre-treatment of myometrium strips with glibenclamide, an inhibitor of ATP-sensitive potassium (KATP) channels, abolished the inhibitory effect of L-cysteine on spontaneous contraction amplitude. The effects of L-cysteine on the amplitude of spontaneous contractions and baseline muscle tone were less potent in labouring tissues than that in nonlabouring strips.Conclusion/SignificanceH2S generated by CSE and CBS locally exerts dual effects on the contractility of pregnant myometrium. Expression of H2S synthetic enzymes is down-regulated during labour, suggesting that H2S is one of the factors involved in the transition of pregnant uterus from quiescence to contractile state after onset of parturition.

Exercise Increases Cystathionine-<i>γ</i>-lyase Expression and Decreases the Status of Oxidative Stress in Myocardium of Ovariectomized Rats

“…Western blot analysis: Protein extraction and Western blot analysis were performed as described previously. 21) Briefly, rat heart tissues were homogenized in cold T-Per lysis buffer (Pierce). Lysates were quickly sonicated in an ice bath and boiled for 5 minutes at 95°C.…”

Dysregulation of Hydrogen Sulfide Producing Enzyme Cystathionine γ-lyase Contributes to Maternal Hypertension and Placental Abnormalities in Preeclampsia

“…Few studies have investigated the functions of CSE/H 2 S in pregnancy. Recently, Patel et al 26,27 demonstrated that both cystathionine β-synthase and CSE are present in human intrauterine tissues and placenta. Given that the placenta is a highly vascular organ, we hypothesize that the dysregulation of the CSE/ H 2 S pathway may contribute to placental abnormalities and a preeclampsia-like condition.…”

Cystathionine β-synthase deficiency causes infertility by impairing decidualization and gene expression networks in uterus implantation sites

“…These metabolic pathways are expressed in different tissues during development. Thus, Cbs is expressed in liver, pregnant myometrium, and decidual tissue, whereas methionine synthase is expressed in all embryonic tissues, the liver being the primary site of activity for these enzymes (48,51,58).Cbs-deficient [Cbs knockout(KO)] mice develop severe Hhcy and provide an extraordinary tool to evaluate its effects during pregnancy. Embryonic development of homozygous animals lacking the enzyme was normal, but there was low birth weight and increased mortality during the postnatal period.…”

“…These metabolic pathways are expressed in different tissues during development. Thus, Cbs is expressed in liver, pregnant myometrium, and decidual tissue, whereas methionine synthase is expressed in all embryonic tissues, the liver being the primary site of activity for these enzymes (48,51,58).…”