Effects of Advancing Gestation and Non-Caucasian Race on Ductus Arteriosus Gene Expression
Effects of Advancing Gestation and Non-Caucasian Race on Ductus Arteriosus Gene Expression
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DOI：
10.1016/j.jpeds.2015.07.011
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发表时间：
2015-11-01
影响因子：
5.1
通讯作者：
Clyman, Ronald I.
中科院分区：
文献类型：
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作者：
Waleh, Nahid;Barrette, Anne Marie;Clyman, Ronald I.
目的 鉴定受人类动脉导管 (DA) 中妊娠提前和种族/民族起源影响的基因。研究设计 我们收集了 3 组妊娠中期的 DA 组织（n = 93、n = 89、n = 91；总共 = 273 个胎儿）。我们检查了四个基因，其 DNA 多态性沿着种族分布，以识别“白种人”和“非白种人”DA。我们使用实时聚合酶链式反应来测量涉及 DA 功能关闭的 48 个候选基因的 RNA 表达，并使用多变量回归分析来检查提前妊娠、“非白种人”种族和基因表达之间的关系。结果 成熟妊娠和非白种人种族是识别接受吲哚美辛治疗时将关闭其专利 DA 的婴儿的重要预测因素。在所有 3 个组织中，妊娠提前持续改变了与氧诱导收缩（例如钙通道、钾通道和内皮素信号传导）、收缩蛋白成熟、组织重塑以及前列腺素和一氧化氮信号传导有关的通路中的基因表达。在“非高加索人”DA 中，与氧诱导收缩有关的通路似乎没有发生改变。两个基因 SLCO2A1 和 NOS3（分别与前列腺素再摄取/代谢和一氧化氮生成有关）在“非白种人”DA 中持续下降。 结论 前列腺素和一氧化氮是反对 DA 关闭的最重要的血管舒张剂。吲哚美辛抑制前列腺素的产生，但不抑制一氧化氮的产生。由于 SLCO2A1 和 NOS3 表达减少可导致前列腺素增加和一氧化氮浓度降低，因此我们推测前列腺素介导的血管舒张可能在维持“非白种人”专利 DA 方面发挥更主导作用，使其在被吲哚美辛抑制时更可能关闭。
Objective To identify genes affected by advancing gestation and racial/ethnic origin in human ductus arteriosus (DA).Study design We collected 3 sets of DA tissue (n = 93, n = 89, n = 91; total = 273 fetuses) from second trimester pregnancies. We examined four genes, with DNA polymorphisms that distribute along racial lines, to identify "Caucasian" and "non-Caucasian" DA. We used real time polymerase chain reaction to measure RNA expression of 48 candidate genes involved in functional closure of the DA, and used multivariable regression analyses to examine the relationships between advancing gestation, "non-Caucasian" race, and gene expression.Results Mature gestation and non-Caucasian race are significant predictors for identifying infants who will close their patent DA when treated with indomethacin. Advancing gestation consistently altered gene expression in pathways involved with oxygen-induced constriction (eg, calcium-channels, potassium-channels, and endothelin signaling), contractile protein maturation, tissue remodeling, and prostaglandin and nitric oxide signaling in all 3 tissue sets. None of the pathways involved with oxygen-induced constriction appeared to be altered in "nonCaucasian" DA. Two genes, SLCO2A1 and NOS3, (involved with prostaglandin reuptake/metabolism and nitric oxide production, respectively) were consistently decreased in "non-Caucasian" DA.Conclusions Prostaglandins and nitric oxide are the most important vasodilators opposing DA closure. Indomethacin inhibits prostaglandin production, but not nitric oxide production. Because decreased SLCO2A1 and NOS3 expression can lead to increased prostaglandin and decreased nitric oxide concentrations, we speculate that prostaglandin-mediated vasodilation may play a more dominant role in maintaining the "non-Caucasian" patent DA, making it more likely to close when inhibited by indomethacin.