EHD1 impaired decidualization of endometrial stromal cells in recurrent implantation failure: role of SENP1 in modulating progesterone receptor signalling†.

Recurrent implantation failure (RIF) patients exhibit poor endometrial receptivity and abnormal decidualization with reduced effectiveness and exposure to progesterone, which is an intractable clinical problem. However, the associated molecular mechanisms remain elusive. We found that EH domain containing 1 (EHD1) expression was abnormally elevated in RIF and linked to aberrant endometrial decidualization. Here we show that EHD1 overexpressed in human endometrial stromal cells significantly inhibited progesterone receptor (PGR) transcriptional activity and the responsiveness to progesterone. No significant changes were observed in PGR mRNA levels, while a significant decrease in progesterone receptor B (PRB) protein level. Indeed, EHD1 binds to the PRB protein, with the K388 site crucial for this interaction. Overexpression of EHD1 promotes the SUMOylation and ubiquitination of PRB, leading to the degradation of the PRB protein. Supplementation with the de-SUMOylated protease SENP1 ameliorated EHD1-repressed PRB transcriptional activity. To establish a functional link between EHD1 and the PGR signalling pathway, sg-EHD1 were utilized to suppress EHD1 expression in HESCs from RIF patients. A significant increase in the expression of prolactin and insulin-like growth factor-binding protein 1 was detected by interfering with the EHD1. In conclusion, we demonstrated that abnormally high expression of EHD1 in endometrial stromal cells attenuated the activity of PRB associated with progesterone resistance in a subset of women with RIF.

Preliminary functional inquiry of lncRNA ENST00000433673 in embryo implantation using bioinformatics analysis.

Long non-coding RNAs (lncRNAs), a class of non-coding RNA, have been shown to be essential in many diseases, such as infertility. Here, we found three candidate lncRNAs, ENST00000414116, ENST00000433673, and ENST00000448179, that are highly expressed in the uterus endometrial tissues of normal patients compared to the tissues of patients with adenomyosis, endometriosis, and recurrent implantation failure. lncRNAs ENST00000414116 and ENST00000433673 showed high expression in endometrial stromal cells (ESCs) and endometrial epithelial cells (EECs), respectively, and lncRNA ENST00000448179 was specifically expressed in ESCs. The bioinformatics analysis results indicated that the target mRNAs of lncRNA ENST00000433673 were related to biological adhesion. Interestingly, intercellular adhesion molecule 1 (ICAM1), an interacting mRNA of the target mRNA integrin subunit alpha L (ITGAL), has been reported be an important regulator of embryo implantation. Further studies found that the target mRNA ITGAL and the interacting mRNA ICAM1 were highly expressed in the uterus endometrial tissues and EECs of normal patients. Based on our results, our study indicates that lncRNA ENST00000433673 might mediate the high expression of the target mRNA ITGAL, thereby promoting the expression of the interacting mRNA ICAM1 and the adhesion of EECs, which facilitates adhesion and implantation between the embryo and the mater. Abbreviations: AMs: adenomyosis; EMs: endometriosis; RIF: recurrent implantation failure; miRNAs: microRNAs; lncRNAs: Long non-coding RNAs; RT-qPCR: real-time quantitative PCR; ESCs: endometrial stromal cells; EECs: endometrial epithelial cells; BFE: free binding energy; PCDHB9: protocadherin beta 9; PARVG: parvin gamma; MAPK6: mitogen-activated protein kinase 6; LAF1: lymphocyte function-associated antigen 1.

In vivo predictors of plaque erosion in patients with ST-segment elevation myocardial infarction: a clinical, angiographical, and intravascular optical coherence tomography study.

Aims: Plaque erosion is a significant substrate of acute coronary thrombosis. This study sought to determine in vivo predictors of plaque erosion in patients with ST-segment elevation myocardial infarction (STEMI). Methods and results: A prospective series of 822 STEMI patients underwent pre-intervention optical coherence tomography. Using established diagnostic criteria, 209 had plaque erosion (25.4%) and 564 had plaque rupture (68.6%). Plaque erosion was more frequent in women <50 years when compared with those ≥50 years of age (P = 0.009). There was a similar, but less striking, trend in men (P = 0.011). Patients with plaque erosion were more frequently current smokers but had fewer other coronary risk factors (dyslipidaemia, hypertension, chronic kidney disease, and diabetes mellitus) than those with plaque rupture. There was a preponderance of plaque erosion in the left anterior descending artery (LAD; 61.2%), whereas plaque rupture was more equally distributed in both the LAD (47.0%) and right coronary artery (43.3%). Despite the similar spatial distribution of erosions and ruptures over the lengths of the coronary arteries, plaque erosion occurred more frequently near a bifurcation (P < 0.001). In the multivariable analysis, age <50 years, current smoking, absence of other coronary risk factors, lack of multi-vessel disease, reduced lesion severity, larger vessel size, and nearby bifurcation were significantly associated with plaque erosion. Nearby bifurcation and current smoking were especially notable in men, while age <50 years was most predictive in women. Conclusions: Plaque erosion was a predictable clinical entity distinct from plaque rupture in STEMI patients, and gender-specific role of risk factors in plaque erosion should be considered.

Chronic kidney disease predicts coronary plaque vulnerability: an optical coherence tomography study.

OBJECTIVE: The addition of cystatin C to creatinine in calculating the estimated glomerular filtration rate (eGFR) is known to improve the risk prediction for cardiovascular events. We sought to investigate the associations between eGFRs calculated by three Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations and coronary plaque phenotype by optical coherence tomography. PATIENTS AND METHODS: We analyzed 181 nonculprit plaques from 116 coronary artery disease patients. For each patient, the eGFR was calculated using the CKD-EPIcreatinine, CKD-EPIcystatin C, and CKD-EPIcombination equations. Patients were divided into three categories according to the eGFR calculated by each equation (≥90, 60-89, and <60 ml/min/1.73 m). RESULTS: The prevalence of thin-cap fibroatheroma (TCFA) was correlated inversely with eGFR calculated using CKD-EPIcystatin C and CKD-EPIcombination equations, but not using the CKD-EPIcreatinine equation. The best cut-off values of eGFR calculated by these two equations for differentiating TCFA were 83 and 84 ml/min/1.73 m, respectively. Compared with the CKD-EPIcreatinine equation, patients who were reclassified upward or downward categories by the CKD-EPIcystatin C equation were associated with consistently lower [adjusted odds ratio=0.27, 95% confidence interval (CI), 0.08-0.86] and higher (adjusted odds ratio=2.41, 95% CI, 1.08-5.41) prevalence for TCFA, respectively. The net reclassification improvement with cystatin C, compared with creatinine, was 0.45 (95% CI, 0.20-0.69) for TCFA, 0.38 (95% CI, 0.09-0.67) for thrombus, and 0.21 (95% CI, 0.00-0.42) for cholesterol crystals. Results were generally similar for the CKD-EPIcombination equation. CONCLUSION: The use of cystatin C alone or in combination with creatinine, compared with creatinine alone, for GFR estimation strengthens the associations between the eGFR and prevalence of vulnerable plaque characteristics.