Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada; and.
Am J Physiol Cell Physiol. 2013 Oct 15;305(8):C803-16. doi: 10.1152/ajpcell.00198.2013. Epub 2013 Aug 15.
Molecular mechanisms involved in uterine quiescence during gestation and those responsible for induction of labor at term are incompletely known. More than 10% of babies born worldwide are premature and 1,000,000 die annually. Preterm labor results in preterm delivery in 50% of cases in the United States explaining 75% of fetal morbidity and mortality. There is no Food and Drug Administration-approved treatment to prevent preterm delivery. Nitric oxide-mediated relaxation of human uterine smooth muscle is independent of global elevation of cGMP following activation of soluble guanylyl cyclase. S-nitrosation is a likely mechanism to explain cGMP-independent relaxation to nitric oxide and may reveal S-nitrosated proteins as new therapeutic targets for the treatment of preterm labor. Employing S-nitrosoglutathione as an nitric oxide donor, we identified 110 proteins that are S-nitrosated in 1 or more states of human pregnancy. Using area under the curve of extracted ion chromatograms as well as normalized spectral counts to quantify relative expression levels for 62 of these proteins, we show that 26 proteins demonstrate statistically significant S-nitrosation differences in myometrium from spontaneously laboring preterm patients compared with nonlaboring patients. We identified proteins that were up-S-nitrosated as well as proteins that were down-S-nitrosated in preterm laboring tissues. Identification and relative quantification of the S-nitrosoproteome provide a fingerprint of proteins that can form the basis of hypothesis-directed efforts to understand the regulation of uterine contraction-relaxation and the development of new treatment for preterm labor.
子宫在妊娠期间静止以及足月时引发分娩的分子机制尚不完全清楚。全世界超过 10%的婴儿是早产儿，每年有 100 万人死亡。在美国，早产导致早产的比例占 50%，占胎儿发病率和死亡率的 75%。目前还没有获得食品和药物管理局批准的治疗方法来预防早产。一氧化氮介导的人子宫平滑肌松弛是可溶性鸟苷酸环化酶激活后 cGMP 全局升高的独立机制。S-亚硝基化可能是解释一氧化氮引起的 cGMP 非依赖性松弛的机制，并可能揭示 S-亚硝基化蛋白作为治疗早产的新治疗靶点。我们使用 S-亚硝基谷胱甘肽作为一氧化氮供体，鉴定了 110 个人类妊娠 1 个或多个状态下的 S-亚硝基化蛋白。使用提取离子色谱图的曲线下面积和标准化谱计数来量化其中 62 种蛋白质的相对表达水平，我们发现与非分娩患者相比，自发性早产分娩患者的子宫肌层中有 26 种蛋白质的 S-亚硝基化差异具有统计学意义。我们鉴定了在早产分娩组织中上调的 S-亚硝基化蛋白和下调的 S-亚硝基化蛋白。S-亚硝基化蛋白质的鉴定和相对定量为理解子宫收缩-松弛的调节以及开发新的早产治疗方法提供了蛋白质指纹图谱。
