A common polymorphism in NR1H2 (LXRbeta) is associated with preeclampsia

Mouzat, Kévin; Mercier, É.; Polge, Anne; Evrard, Alexandre; Baron, Silvère; Balducchi, Jean-Pierre; Brouillet, Jean‐Paul; Lumbroso, Serge; Gris, Jean‐Christophe

doi:10.1186/1471-2350-12-145

Cited by 23 publications

(14 citation statements)

References 41 publications

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“…This is in agreement with the association between a common polymorphism in the LXR-␤ gene and preeclampsia, 44 the increase in sEng in preeclampsia, and the reported pathogenic role of sEng in hypertension. Further support for this hypothesis was obtained from transgenic mice overexpressing human sEng that displayed a clear increase in arterial pressure associated with high levels of circulating sEng ( Figure 6F).…”

Section: Valbuena-diez Et Al Oxysterol-induced Soluble Endoglin In Hysupporting

confidence: 79%

Oxysterol-Induced Soluble Endoglin Release and Its Involvement in Hypertension

et al. 2012

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Background-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. Methods and Results-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. Conclusions-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. (Circulation. 2012;126:2612-2624.)Key Words: cell hypoxia Ⅲ hypertension Ⅲ pre-eclampsia Ⅲ pregnancy Ⅲ peptides P reeclampsia is a pregnancy-specific syndrome characterized by systemic hypertension, proteinuria, and edema in the third trimester of pregnancy. 1,2 It affects both the fetus and the mother and occurs in Ϸ5% of pregnancies. Severe preeclampsia leads to the appearance of the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), seizures, or fetal growth restriction and can result in fetal death. Preeclampsia is thought to be the consequence of impaired placentation resulting from inadequate trophoblastic invasion of the maternal spiral arteries. 3 Abnormal placentation is an important predisposing factor for preeclampsia, whereas endothelial dysfunction appears to be central to the pathophysiological changes, possibly indicative of a 2-stage disorder characterized by reduced placental perfusion and a maternal syndrome. Hypoxia, followed by oxidative stress, has been postulated as a critical signal that initiates the pathogenic process in preeclampsia. 4,5 Hypoxia and extracellular inflammatory signals can induce the intracellular accumulation of reactive oxygen species (ROS). 6,7 In turn, the imbalance between ROS production and antioxidant systems induces oxidative stress that negatively affects reproductive processes, including cyclic luteal and endometrial changes, follicular d...

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Section: Valbuena-diez Et Al Oxysterol-induced Soluble Endoglin In Hysupporting

confidence: 79%

Oxysterol-Induced Soluble Endoglin Release and Its Involvement in Hypertension

et al. 2012

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“…These observations suggest that EZH2 deregulation could be linked to a mechanism specifically depending on LXRβ. Such specificity has already been shown in human, particularly in a study on preeclampsia providing a LXRβ-dependent risk in this pathology [39]. Another point emphasized by the human dataset is the absence of NKX3.1 expression changes between normal prostate, carcinoma and metastasis group in both examined cohorts (Figure S8).…”

Section: Discussionsupporting

confidence: 64%

Liver X Receptors Protect from Development of Prostatic Intra-Epithelial Neoplasia in Mice

et al. 2013

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LXR (Liver X Receptors) act as “sensor” proteins that regulate cholesterol uptake, storage, and efflux. LXR signaling is known to influence proliferation of different cell types including human prostatic carcinoma (PCa) cell lines. This study shows that deletion of LXR in mouse fed a high-cholesterol diet recapitulates initial steps of PCa development. Elevation of circulating cholesterol in Lxrαβ-/- double knockout mice results in aberrant cholesterol ester accumulation and prostatic intra-epithelial neoplasia. This phenotype is linked to increased expression of the histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2), which results in the down-regulation of the tumor suppressors Msmb and Nkx3.1 through increased methylation of lysine 27 of histone H3 (H3K27) on their promoter regions. Altogether, our data provide a novel link between LXR, cholesterol homeostasis, and epigenetic control of tumor suppressor gene expression.

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“…Over the past year, liver X receptor-β (NR1H2), a key player in lipid metabolism, has been implicated in preeclampsia through modulation of trophoblast invasion and regulation of the expression of the endoglin (CD105) gene, a marker of preeclampsia [26]. The PROMISSE study was the first to look at specific genetic risk factors that may predispose SLE patients to preeclampsia.…”

Section: Reviewmentioning

confidence: 99%