MicroRNA-210 Targets Ten-Eleven Translocation Methylcytosine Dioxygenase 1 and Suppresses Pregnancy-Mediated Adaptation of Large Conductance Ca2+-Activated K+ Channel Expression and Function in Ovine Uterine Arteries
MicroRNA-210 Targets Ten-Eleven Translocation Methylcytosine Dioxygenase 1 and Suppresses Pregnancy-Mediated Adaptation of Large Conductance Ca2+-Activated K+ Channel Expression and Function in Ovine Uterine Arteries
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DOI：
10.1161/hypertensionaha.117.09864
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发表时间：
2017-09-01
期刊：
影响因子：
8.3
通讯作者：
Zhang, Lubo
中科院分区：
文献类型：
--
作者：
Hu, Xiang-Qun;Dasgupta, Chiranjib;Zhang, Lubo
妊娠低氧抑制大电导钙激活钾通道(BKCa)的表达及其在子宫动脉妊娠适应性中的作用。鉴于在妊娠和子痫前期的低氧中，microRNA-210(miR-210)的表达增加，本研究试图探讨miR-210在子宫动脉BKCa通道适应性调节中的作用。妊娠低氧显著增加妊娠绵羊子宫血管阻力和血压，并上调子宫动脉miR-210的表达。MIR-210可与绵羊子宫动脉中的甲基胞嘧啶双加氧酶1mRNA3‘非翻译区结合，减少妊娠绵羊子宫动脉中甲基胞嘧啶双加氧酶1mRNA和蛋白的丰度，并能抑制激素诱导的非妊娠动物子宫动脉中甲基胞嘧啶双加氧酶1的表达。相应地，miR-210阻断了妊娠和类固醇激素诱导的子宫动脉BKCa通道β(1)亚单位表达的上调。在功能上，miR-210抑制妊娠绵羊子宫动脉肌细胞BKCa通道电流密度，并抑制类固醇激素引起的非妊娠动物子宫动脉BKCa通道电流的增加。阻断内源性miR-210可抑制缺氧对BKCa通道活性的抑制。此外，miR-210可降低BKCa通道介导的舒张性，增加子宫动脉的压力依赖性肌源性张力。这些结果表明，miR-210在子宫动脉10-11易位甲基胞嘧啶双加氧酶1的下调和BKCa通道功能的抑制中起重要作用，揭示了妊娠低氧和先兆子痫子宫血流动力学适应不良的表观遗传调节新机制。
Gestational hypoxia inhibits large conductance Ca2+-activated K+ (BKCa) channel expression and function in uterine arterial adaptation to pregnancy. Given the findings that microRNA-210 (miR-210) is increased in hypoxia during gestation and preeclampsia, the present study sought to investigate the role of miR-210 in the regulation of BKCa channel adaptation in the uterine artery. Gestational hypoxia significantly increased uterine vascular resistance and blood pressure in pregnant sheep and upregulated miR-210 in uterine arteries. MiR-210 bound to ovine ten-eleven translocation methylcytosine dioxygenase 1 mRNA 3' untranslated region and decreased ten-eleven translocation methylcytosine dioxygenase 1 mRNA and protein abundance in uterine arteries of pregnant sheep, as well as abrogated steroid hormone-induced upregulation of ten-eleven translocation methylcytosine dioxygenase 1 expression in uterine arteries of nonpregnant animals. In accordance, miR-210 blocked pregnancy-and steroid hormone-induced upregulation of BKCa channel beta(1) subunit expression in uterine arteries. Functionally, miR-210 suppressed BKCa channel current density in uterine arterial myocytes of pregnant sheep and inhibited steroid hormone-induced increases in BKCa channel currents in uterine arteries of nonpregnant animals. Blockade of endogenous miR-210 inhibited hypoxia-induced suppression of BKCa channel activity. In addition, miR-210 decreased BKCa channel-mediated relaxations and increased pressure-dependent myogenic tone of uterine arteries. Together, the results demonstrate that miR-210 plays an important role in the downregulation of ten-eleven translocation methylcytosine dioxygenase 1 and repression of BKCa channel function in uterine arteries, revealing a novel mechanism of epigenetic regulation in the maladaptation of uterine hemodynamics in gestational hypoxia and preeclampsia.