t0901317 and Pre-Eclampsia

Ischemia in the placenta is considered the base of the pathogenesis of preeclampsia, a pregnancy-specific syndrome in which soluble endoglin (sEng) is a prognostic marker and plays a pathogenic role. Here, we investigated the effects of hypoxia and the downstream pathways in the release of sEng.. Under hypoxic conditions, the trophoblast-like cell line JAR showed an increase in sEng parallel to an elevated formation of reactive oxygen species. Because reactive oxygen species are related to the formation of oxysterols, we assessed the effect of 22-(R)-hydroxycholesterol, a natural ligand of the liver X receptor (LXR), and the LXR synthetic agonist T0901317. Treatment of JAR cells or human placental explants with 22-(R)-hydroxycholesterol or T0901317 resulted in a clear increase in sEng that was dependent on LXR. These LXR agonists induced an increased matrix metalloproteinase-14 expression and activity and a significant reduction of its endogenous inhibitor, tissue inhibitor of metalloproteinase-3. In addition, mice treated with LXR agonists underwent an increase in the plasma sEng levels, concomitant with an increase in arterial pressure. Moreover, transgenic mice overexpressing sEng displayed high blood pressure. Finally, administration of an endoglin peptide containing the consensus matrix metalloproteinase-14 cleavage site G-L prevented the oxysterol-dependent increase in arterial pressure and sEng levels in mice.. These studies provide a clue to the involvement of the LXR pathway in sEng release and its pathogenic role in vascular disorders such as preeclampsia.

Topics: Animals; Anticholesteremic Agents; Antigens, CD; Blood Pressure; Cell Line, Tumor; Choriocarcinoma; Endoglin; Female; Human Umbilical Vein Endothelial Cells; Humans; Hydrocarbons, Fluorinated; Hydroxycholesterols; Intracellular Signaling Peptides and Proteins; Ischemia; Liver X Receptors; Male; Matrix Metalloproteinase 14; Mice; Mice, Inbred C57BL; Mice, Transgenic; Orphan Nuclear Receptors; Placenta Diseases; Pre-Eclampsia; Pregnancy; Receptors, Cell Surface; Sulfonamides; Tissue Inhibitor of Metalloproteinase-3; Uterine Neoplasms

The Liver X receptors (LXR) alpha and beta and their target genes such as the ATP-binding cassette (ABC) transporters have been shown to be crucially involved in the regulation of cellular cholesterol homeostasis. The aim of this study was to characterize the role of LXR alpha/beta in the human placenta under normal physiological circumstances and in preeclampsia.. We investigated the expression pattern of the LXRs and their target genes in the human placenta during normal pregnancy and in preeclampsia. Placental explants and cell lines were studied under different oxygen levels and pharmacological LXR agonists.. Gene expressions (Taqman PCR) and protein levels (Western Blot) were combined with immunohistochemistry to analyze the expression of LXR and its target genes.. In the human placenta, LXRA and LXRB expression increased during normal pregnancy. This was paralleled by the expression of their prototypical target genes, e.g., the cholesterol transporter ABCA1. Interestingly, early-onset preeclamptic placentae revealed a significant upregulation of ABCA1. Culture of JAr trophoblast cells and human first trimester placental explants under low oxygen lead to increased expression of LXRA and ABCA1 which was further enhanced by the LXR agonist T0901317.. LXRA together with ABCA1 are specifically expressed in the human placenta and can be regulated by hypoxia. Deregulation of this system in early preeclampsia might be the result of placental hypoxia and hence might have consequences for maternal-fetal cholesterol transport.

Topics: Anticholesteremic Agents; ATP-Binding Cassette Transporters; Cell Line, Tumor; Cholesterol; Female; Gene Expression Regulation, Developmental; Humans; Hydrocarbons, Fluorinated; Hypoxia; Immunoblotting; Immunohistochemistry; In Vitro Techniques; Liver X Receptors; Orphan Nuclear Receptors; Oxygen; Placenta; Pre-Eclampsia; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; RNA; Statistics, Nonparametric; Sulfonamides; Trophoblasts

Human implantation involves invasion of the uterine wall and remodeling of uterine arteries by extravillous cytotrophoblasts. Defects in these early steps of placental development lead to poor placentation and are often associated with preeclampsia, a frequent complication of human pregnancy. One of the complex mechanisms controlling trophoblast invasion involves the activation of the liver X receptor beta (or NR1H2, more commonly known as LXRbeta) by oxysterols known as potent LXR activators. This activation of LXRbeta leads to a decrease of trophoblast invasion. The identification of new target genes of LXR in the placenta could aid in the understanding of their physiological roles in trophoblast invasion. In the present study, we show that the endoglin (ENG) gene is a direct target of the liver X receptor alpha (NR1H3, also known as LXRalpha). ENG, whose gene is highly expressed in syncytiotrophoblasts, is part of the transforming growth factor (TGF) receptor complex that binds several members of the TGFbeta superfamily. In the human placenta, ENG has been shown to be involved in the inhibition of trophoblast invasion. Treatment of human choriocarcinoma JAR cells with T0901317, a synthetic LXR-selective agonist, leads to a significant increase in ENG mRNA and protein levels. Using transfection and electrophoretic mobility shift assays, we demonstrate that LXR (as a heterodimer with the retinoid X receptor) is able to bind the ENG promoter on an LXR response element and mediates the activation of ENG gene expression by LXRalpha in JAR cells. This study suggests a novel mechanism by which LXR may regulate trophoblast invasion in pathological pregnancy such as preeclampsia.

Topics: Antigens, CD; Base Sequence; Binding Sites; Cell Line; DNA; DNA Primers; DNA-Binding Proteins; Embryo Implantation; Endoglin; Female; Gene Expression Regulation; Humans; Hydrocarbons, Fluorinated; Ligands; Liver X Receptors; Orphan Nuclear Receptors; Pre-Eclampsia; Pregnancy; Promoter Regions, Genetic; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear; Retinoid X Receptors; RNA, Messenger; Sulfonamides; Trophoblasts