Mari Ujita

ATP-binding cassette transporter A1 expression is decreased in preeclamptic placentas.

Preeclampsia is a pregnancy-specific multisystem disorder characterized by hypertension and proteinuria. Accentuated maternal hyperlipidemia, especially high serum levels of oxidized low-density lipoprotein (oxLDL), is one of the features of preeclampsia. We previously reported that lectin-like oxidized LDL receptor 1 (LOX-1) expression was decreased in preeclamptic placentas. Here, we show that decreased LOX-1 expression is associated with low expression of adenosine triphosphate-binding cassette transporter A1 (ABCA1) in the placenta. The ABCA1 mediates cellular efflux of cholesterol, and liver X receptors (LXRs) are its predominant transcriptional regulators. Both ABCA1 and LXR expressions were significantly lower in preeclamptic placentas than those in normal controls. Oxidized LDL upregulated ABCA1 expression, while LOX-1 blockade resulted in the alleviation of increasing ABCA1 messenger RNA in JAR cells. These results suggest that low LOX-1 expression may lead to insufficient oxLDL uptake, thereby contributing to reduced LXR activation and decreased ABCA1 expression in preeclamptic placentas.

Reliable pre-eclampsia pathways based on multiple independent microarray data sets

Pre-eclampsia is a multifactorial disorder characterized by heterogeneous clinical manifestations. Gene expression profiling of preeclamptic placenta have provided different and even opposite results, partly due to data compromised by various experimental artefacts. Here we aimed to identify reliable pre-eclampsia-specific pathways using multiple independent microarray data sets. Gene expression data of control and preeclamptic placentas were obtained from Gene Expression Omnibus. Single-sample gene-set enrichment analysis was performed to generate gene-set activation scores of 9707 pathways obtained from the Molecular Signatures Database. Candidate pathways were identified by t-test-based screening using data sets, GSE10588, GSE14722 and GSE25906. Additionally, recursive feature elimination was applied to arrive at a further reduced set of pathways. To assess the validity of the pre-eclampsia pathways, a statistically-validated protocol was executed using five data sets including two independent other validation data sets, GSE30186, GSE44711. Quantitative real-time PCR was performed for genes in a panel of potential pre-eclampsia pathways using placentas of 20 women with normal or severe preeclamptic singleton pregnancies (n = 10, respectively). A panel of ten pathways were found to discriminate women with pre-eclampsia from controls with high accuracy. Among these were pathways not previously associated with pre-eclampsia, such as the GABA receptor pathway, as well as pathways that have already been linked to pre-eclampsia, such as the glutathione and CDKN1C pathways. mRNA expression of GABRA3 (GABA receptor pathway), GCLC and GCLM (glutathione metabolic pathway), and CDKN1C was significantly reduced in the preeclamptic placentas. In conclusion, ten accurate and reliable pre-eclampsia pathways were identified based on multiple independent microarray data sets. A pathway-based classification may be a worthwhile approach to elucidate the pathogenesis of pre-eclampsia.

Simvastatin inhibits oxidative stress via the activation of nuclear factor erythroid 2‐related factor 2 signaling in trophoblast cells

Nuclear factor erythroid 2‐related factor 2 (Nrf2) is a key transcriptional regulator against oxidative stress through the induction of antioxidant and cytoprotective genes, such as heme oxygenase 1 (HO‐1), glutamyl cysteine ligase catalytic (GCLC), and glutamyl cysteine ligase modulatory (GCLM). Nrf2 signaling is disrupted in pre‐eclamptic placentas, although increased oxidative stress is implicated in pre‐eclampsia. The aims of the study were: (i) to investigate the mechanism that underlies the impaired Nrf2 signaling in pre‐eclamptic placentas, and (ii) to examine the potential therapeutic role of statin for pre‐eclampsia.

Impaired Wnt5a signaling in extravillous trophoblasts: Relevance to poor placentation in early gestation and subsequent preeclampsia

BACKGROUND Defective decidual endovascular trophoblast invasion and subsequent impaired spiral artery remodeling is highly associated with the pathogenesis of preeclampsia (PE). Since there are scant and conflicting data regarding the function of Wnt5a signaling in extravillous trophoblasts (EVT), the aim of this study was to investigate whethere impaired Wnt5a signaling affects the invasive and tube forming capabilities of EVT. METHODS Expression levels of Wnt ligands were compared between first trimester chorionic villi of women who later developed PE and women with unaffected pregnancies using publicly available microarray data (GSE12767). Wnt5a expression was examined in placentas using quantitative RT-PCR, Western blot analysis and immunohistochemistry. The function of Wnt5a signaling in EVT was investigated in an immortalized first trimester EVT cell line, HTR-8/SVneo, using small-interfering RNAs, recombinant human Wnt5a (rhWnt5a), and inhibitors of JNK or PKC. RESULTS Microarray data analysis of the first trimester placentas showed that, among Wnt ligands, Wnt5a expression was significantly lower in women who later developed PE. The mRNA and protein expression levels of Wnt5a were significantly decreased in PE placentas compared with normal term placentas. Wnt5a knockdown significantly suppressed invasion and tube formation of HTR-8/SVneo cells, while the addition of rhWnt5a augmented the cell migration, invasion, and tube formation. Repression of Wnt5a/PKC signaling in HTR-8/SVneo cells inhibited cell invasion, but did not alter cell tube formation. In contrast, inhibition of Wnt5a/JNK signaling attenuated rhWnt5a-induced invasion and tube formation capabilities. CONCLUSIONS These findings suggest that impaired Wnt5a signaling is associated with poor placentation and subsequent PE.

An attempt to simplify total laparoscopic hysterectomy procedures at our hospital

Objective: We are currently testing a simplified and safe laparoscopic hysterectomy procedure in our clinical practice that is technically similar to laparotomy. The present study aimed to evaluate the feasibility of this modified total laparoscopic hysterectomy (TLH) method, which uses the RUMI II Colpotomiser System and without requiring separation of the ureter and uterine artery for laparoscopic surgeons under training. Methods: During the procedure, uterine vessels and ureters are not skeletonized, the vaginal vault is identified using a colpotomy cup, and retrograde dissection is performed from the anterior vaginal wall. We used statistical analysis to evaluate operative time, parity, body mass index (BMI), blood loss, and surgery-related complications by Students t-test. Results: We have performed 11 TLH procedures applying the above method, excluding cases of severe adhesion, since 2016. Compared with the traditional TLH method, average operating time was significantly shorter using the new method. There was no significant difference between the two groups with regards to parity, BMI, or blood loss. No complications have occurred postoperatively since 2016; whereas, one vesicovaginal fistula occurred in the 18 TLH performed before 2016. Conclusion: This simplified TLH procedure may be a safe and effective alternative for laparoscopic beginners as it is similar to that of abdominal hysterectomy. Furthermore, the exclusion of complicated tissue peeling reduces operator stress and surgery-related complications.