β3-肾上腺素能激动剂可对抗胎盘细胞的氧化应激和 Na+-K+ 泵抑制性 S-谷胱甘肽化:对子痫前期的影响。

IF 5 2区 生物学 Q2 CELL BIOLOGY
Chia-Chi Liu, Yunjia Zhang, Yeon Jae Kim, Elisha J Hamilton, Bei Xu, Jane Limas, Sharon A McCracken, Jonathan M Morris, Angela Makris, Annemarie Hennessy, Helge H Rasmussen
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引用次数: 0

摘要

子痫前期胎盘缺血/再灌注和缺氧/再氧合(H/R)引起的氧化应激伴随着Na+-K+泵抑制及其β1亚基(GSS-β1)的S-谷胱甘肽化,这种修饰可抑制该泵。β3-肾上腺素能受体(β3-AR)激动剂能逆转 GSS-β1。我们研究了激动剂 CL316,243 对 GSS-β1 的影响以及 H/R 诱导的氧化应激在永生化的人类前三个月滋养层细胞(HTR-8/SVneo)和从正常足月妊娠新鲜分离的胎盘外植体中的来源。H/R增加了GSS-β1,并减少了α1/β1泵亚基的共免疫沉淀,这反映了α1/β1亚基相互作用受到损害。H/R 增加了 p47phox/p22phox NADPH 氧化酶亚基的共沉淀,反映了激活 NADPH 氧化酶所需的细胞膜 p47phox 的膜转运。对 O2 敏感的二氢乙锭的荧光也同时增加。H/R增加了内皮一氧化氮合酶(GSS-eNOS)的S-谷胱甘肽化,从而解除了NO合成与O2合成的耦合,并减少了滋养细胞的迁移。肿瘤坏死因子α(TNF-α)诱导的氧化应激增加了可溶性fms样酪氨酸激酶受体1(sFlt-1)滋养细胞的释放(子痫前期的标志物),并减少了滋养细胞与内皮细胞网络的整合。CL316,243消除了H/R诱导的GSS-β1和α1/β1亚基共沉淀的减少,消除了NADPH氧化酶的激活和GSS-eNOS的增加,恢复了滋养细胞的迁移,消除了sFlt-1释放的增加,恢复了滋养细胞与内皮细胞网络的整合。H/R诱导的GSS-β1、α1/β1亚基共免疫沉淀和胎盘外植体的NADPH氧化酶活化反映了H/R对滋养层细胞的影响,而CL316,243消除了这些变化。我们得出的结论是,β3-AR 激动剂可在体外对抗子痫前期的主要病理生理特征。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
β3-adrenergic agonist counters oxidative stress and Na+-K+ pump inhibitory S-glutathionylation of placental cells: implications for preeclampsia.

Oxidative stress from placental ischemia/reperfusion and hypoxia/reoxygenation (H/R) in preeclampsia is accompanied by Na+-K+ pump inhibition and S-glutathionylation of its β1 subunit (GSS-β1), a modification that inhibits the pump. β3-adrenergic receptor (β3-AR) agonists can reverse GSS-β1. We examined the effects of the agonist CL316,243 on GSS-β1 and sources of H/R-induced oxidative stress in immortalized first-trimester human trophoblast (HTR-8/SVneo) and freshly isolated placental explants from normal-term pregnancies. H/R increased GSS-β1 and, reflecting compromised α1/β1 subunit interaction, reduced α1/β1 pump subunit coimmunoprecipitation. H/R increased p47phox/p22phox NADPH oxidase subunit coimmunoprecipitation, reflecting membrane translocation of cytosolic p47phox that is needed to activate NADPH oxidase. Fluorescence of O2•--sensitive dihydroethidium increased in parallel. H/R increased S-glutathionylation of endothelial nitric oxide synthase (GSS-eNOS) that uncouples nitric oxide synthesis toward the synthesis of O2•- and reduced trophoblast migration. Oxidative stress induced by tumor necrosis factor α increased soluble fms-like tyrosine kinase receptor 1 (sFlt-1) trophoblast release, a marker of preeclampsia, and reduced trophoblast integration into endothelial cellular networks. CL316,243 eliminated H/R-induced GSS-β1 and decreases of α1/β1 subunit coimmunoprecipitation, eliminated NADPH oxidase activation and increases in GSS-eNOS, restored trophoblast migration, eliminated increased sFlt-1 release, and restored trophoblast integration in endothelial cell networks. H/R-induced GSS-β1, α1/β1 subunit coimmunoprecipitation, and NADPH oxidase activation of placental explants reflected effects of H/R for trophoblasts and CL316,243 eliminated these changes. We conclude a β3-AR agonist counters key pathophysiological features of preeclampsia in vitro. β3 agonists already in human use for another purpose are potential candidates for repurposing to treat preeclampsia.NEW & NOTEWORTHY H/R-induced oxidative stress and deficient NO-dependent placentation are features of preeclampsia, yet nonspecific antioxidants and NO donors are ineffective. Here, activation of the microdomain-confined signaling pathway with an agonist for the eNOS-coupled β3-AR eliminates inhibitory glutathionylation of the Na+-K+ pump's β1 subunit, uncoupling of eNOS, and activation of NADPH oxidase that are sources of H/R-induced oxidative stress. The agonist also eliminates H/R-induced inhibition of trophoblast migration and their integration into an endothelial network.

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来源期刊
CiteScore
9.10
自引率
1.80%
发文量
252
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.
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