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ATP-binding cassette transporter A1 (ABCA1) plays a critical role in maintaining cellular cholesterol homeostasis. The purpose of this study is to identify the molecular mechanism(s) underlying ABCA1 epigenetic modification and determine its potential impact on ABCA1 expression in macrophage-derived foam cell formation and atherosclerosis development. DNA methylation induced foam cell formation from macrophages and promoted atherosclerosis in apolipoprotein E-deficient (apoE−/−) mice. Bioinformatics analyses revealed a large CpG island (CGI) located in the promoter region of ABCA1. Histone methyltransferase enhancer of zeste homolog 2 (EZH2) downregulated ABCA1 mRNA and protein expression in THP-1 and RAW264.7 macrophage-derived foam cells. Pharmacological inhibition of DNA methyltransferase 1 (DNMT1) with 5-Aza-dC or knockdown of DNMT1 prevented the downregulation of macrophage ABCA1 expression, suggesting a role of DNA methylation in ABCA1 expression. Polycomb protein EZH2 induced DNMT1 expression and methyl-CpG-binding protein-2 (MeCP2) recruitment, and stimulated the binding of DNMT1 and MeCP2 to ABCA1 promoter, thereby promoting ABCA1 gene DNA methylation and atherosclerosis. Knockdown of DNMT1 inhibited EZH2-induced downregulation of ABCA1 in macrophages. Conversely, EZH2 overexpression stimulated DNMT1-induced ABCA1 gene promoter methylation and atherosclerosis. EZH2-induced downregulation of ABCA1 gene expression promotes foam cell formation and the development of atherosclerosis by DNA methylation of ABCA1 gene promoter. [ABSTRACT FROM AUTHOR]

Background: The optimal mode of delivery in twin pregnancies remains controversial. A recent randomized trial did not find any benefit of planned cesarean vs. vaginal delivery at 32–38 weeks gestation, but the trial was not powered to detect a moderate effect. We aimed to evaluate the impact of cesarean delivery on perinatal mortality and severe neonatal morbidity in twin pregnancies at ≥32 weeks through a large database exploration approach with the power to detect moderate risk differences. Methods: In a retrospective birth cohort study using the U.S. matched multiple births, 1995–2000 (the available largest multiple birth dataset), we compared perinatal outcomes in twins (n = 181,810 pregnancies) delivered at 32–41 weeks gestation without congenital anomalies. The primary outcome was a composite of perinatal death and severe neonatal morbidity. Cox regression was used to estimate the adjusted hazard ratio (aHR) controlling for the propensity to cesarean delivery, fetal characteristics (sex, birth weight, birth weight discordance, same-sex twin or not) and twin-cluster level dependence. Prospective risks were calculated using the fetuses-at-risk denominators. Results: The overall rates of the primary outcome were slightly lower in intended cesarean (6.20%) vs. vaginal (6.45%) deliveries. The aHRs of the primary outcome were in favor of vaginal delivery at 32 (aHR = 1.06, p = 0.03) or 33 (aHR = 1.22, p<0.001) weeks, neutral at 34–35 weeks, but in favor of cesarean delivery at 36 (aHR = 0.94, p = 0.004), 37, 38 and 39+ weeks (aHR: 0.72 to 0.78, all p<0.001). The lower risk of the primary outcome for cesarean vs. vaginal deliveries at 36+ weeks of gestation remained when the analyses were restricted to different-sex (dichorionic) twins (aHR = 0.84, 95% CI 0.80–0.88). Conclusion: Cesarean delivery may be beneficial for perinatal outcomes overall in twin pregnancies at ≥36 weeks gestation. [ABSTRACT FROM AUTHOR]