Kim Joohwan, Lee Kyu-Sun, Kim Ji-Hee, Lee Dong-Keon, Park Minsik, Choi Seunghwan, Park Wonjin, Kim Suji, Choi Yoon Kyung, Hwang Jong Yun, Choe Jongseon, Won Moo-Ho, Jeoung Dooil, Lee Hansoo, Ryoo Sungwoo, Ha Kwon-Soo, Kwon Young-Guen, Kim Young-Myeong
Departments of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea.
Departments of Obstetrics and Gynecology, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea.
Free Radic Biol Med. 2017 Mar;104:185-198. doi: 10.1016/j.freeradbiomed.2017.01.010. Epub 2017 Jan 11.
Preeclampsia is an inflammatory disease with endothelial cell dysfunction that occurs via decreased endothelial nitric oxide synthase/nitric oxide (eNOS/NO) activity. Aspirin reduces the incidence of hypertensive pregnancy complications. However, the underlying mechanism has not been clearly explained. Here, we found that tumor necrosis factor (TNF)-α, microRNA (miR)-155, and eNOS levels as well as endothelial redox phenotype were differentially regulated in preeclamptic patients, implying the involvement of TNF-α- and redox signal-mediated miR-155 biogenesis and eNOS downregulation in the pathogenesis of preeclampsia. Aspirin prevented the TNF-α-mediated increase in miR-155 biogenesis and decreases in eNOS expression and NO/cGMP production in cultured human umbilical vein endothelial cells (HUVECs). Similar effects of aspirin were also observed in HUVECs treated with HO. The preventive effects of aspirin was associated with the inhibition of nuclear factor-κB (NF-κB)-dependent MIR155HG (miR-155 host gene) expression. Aspirin recovered the TNF-α-mediated decrease in wild-type, but not mutant, eNOS 3'-untranslated region reporter activity, whose effect was blocked by miR-155 mimic. Moreover, aspirin prevented TNF-α-mediated endothelial cell dysfunction associated with impaired vasorelaxation, angiogenesis, and trophoblast invasion, and the preventive effects were blocked by miR-155 mimic or an eNOS inhibitor. Aspirin rescued TNF-α-mediated eNOS downregulation coupled with endothelial dysfunction by inhibiting NF-κB-dependent transcriptional miR-155 biogenesis. Thus, the redox-sensitive NF-κB/miR-155/eNOS axis may be crucial in the pathogenesis of vascular disorders including preeclampsia.
子痫前期是一种伴有内皮细胞功能障碍的炎症性疾病，其发生是由于内皮型一氧化氮合酶/一氧化氮（eNOS/NO）活性降低。阿司匹林可降低高血压妊娠并发症的发生率。然而，其潜在机制尚未得到明确解释。在此，我们发现子痫前期患者体内肿瘤坏死因子（TNF）-α、微小RNA（miR）-155和eNOS水平以及内皮氧化还原表型存在差异调节，这意味着TNF-α和氧化还原信号介导的miR-155生物合成及eNOS下调参与了子痫前期的发病机制。阿司匹林可防止TNF-α介导的培养人脐静脉内皮细胞（HUVECs）中miR-155生物合成增加以及eNOS表达和NO/cGMP生成减少。在用HO处理的HUVECs中也观察到了阿司匹林的类似作用。阿司匹林的预防作用与抑制核因子-κB（NF-κB）依赖性MIR155HG（miR-155宿主基因）表达有关。阿司匹林恢复了TNF-α介导的野生型而非突变型eNOS 3'-非翻译区报告基因活性的降低，其作用被miR-155模拟物阻断。此外，阿司匹林可防止TNF-α介导的与血管舒张、血管生成和滋养层细胞侵袭受损相关的内皮细胞功能障碍，且这些预防作用被miR-155模拟物或eNOS抑制剂阻断。阿司匹林通过抑制NF-κB依赖性转录性miR-155生物合成，挽救了TNF-α介导的eNOS下调及内皮功能障碍。因此，氧化还原敏感的NF-κB/miR-155/eNOS轴可能在包括子痫前期在内的血管疾病发病机制中起关键作用。
