Department of Internal Medicine, Division of Nephrology and Hypertension, Scott & White Healthcare/Texas A&M Health Science Center, Temple, Texas, USA.
PLoS One. 2013 Jul 2;8(7):e67760. doi: 10.1371/journal.pone.0067760. Print 2013.
Several clinical studies have reported increased placental miR-210 expression in women with PE compared to normotensive women, but whether miR-210 plays a role in the etiology of PE is unknown. We reported that activation of TLR3 produces the PE-like symptoms of hypertension, endothelial dysfunction, and proteinuria in mice only when pregnant, but whether TLR3 activation in pregnant mice and human cytotrophoblasts (CTBs) increases miR-210 and modulates its targets related to inflammation are unknown. Placental miR-210 levels were increased significantly in pregnant mice treated with the TLR3 agonist poly I:C (P-PIC). Both HIF-1α and NF-κBp50, known to bind the miR-210 promoter and induce its expression, were also increased significantly in placentas of P-PIC mice. Target identification algorithms and gene ontology predicted STAT6 as an inflammation-related target of miR-210 and STAT6 was decreased significantly in placentas of P-PIC mice. IL-4, which is regulated by STAT6 and increases during normotensive pregnancy, failed to increase in serum of P-PIC mice. P-PIC TLR3 KO mice did not develop hypertension and placental HIF-1α, NF-κBp50, miR-210, STAT6, and IL-4 levels were unchanged. To determine the placental etiology, treatment of human CTBs with poly I:C significantly increased HIF-1α, NF-κBp50, and miR-210 levels and decreased STAT6 and IL-4 levels. Overexpression of miR-210 in CTBs decreased STAT6 and IL-4 while inhibition of miR-210 increased STAT6 and IL-4. These findings demonstrate that TLR3 activation induces placental miR-210 via HIF-1α and NF-κBp50 leading to decreased STAT6 and IL-4 levels and this may contribute to the development of PE.
几项临床研究报告称，与正常血压孕妇相比，PE 孕妇的胎盘 miR-210 表达增加，但 miR-210 是否在 PE 的病因中起作用尚不清楚。我们报道称，TLR3 的激活仅在怀孕时会在小鼠中产生类似于 PE 的高血压、内皮功能障碍和蛋白尿症状，但 TLR3 在怀孕小鼠和人绒毛滋养细胞 (CTB) 中的激活是否会增加 miR-210 并调节其与炎症相关的靶标尚不清楚。TLR3 激动剂 poly I:C (P-PIC) 处理的怀孕小鼠的胎盘 miR-210 水平显著增加。众所周知，结合 miR-210 启动子并诱导其表达的 HIF-1α 和 NF-κBp50 在 P-PIC 小鼠的胎盘中也显著增加。靶标识别算法和基因本体预测 STAT6 是 miR-210 的炎症相关靶标，并且 P-PIC 小鼠的胎盘中 STAT6 显著减少。受 STAT6 调节并在正常妊娠期间增加的 IL-4 在 P-PIC 小鼠的血清中未能增加。P-PIC TLR3 KO 小鼠未发生高血压，胎盘 HIF-1α、NF-κBp50、miR-210、STAT6 和 IL-4 水平不变。为了确定胎盘病因，用 poly I:C 处理人 CTB 可显著增加 HIF-1α、NF-κBp50 和 miR-210 水平，降低 STAT6 和 IL-4 水平。CTB 中 miR-210 的过表达降低了 STAT6 和 IL-4，而 miR-210 的抑制增加了 STAT6 和 IL-4。这些发现表明，TLR3 的激活通过 HIF-1α 和 NF-κBp50 诱导胎盘 miR-210，导致 STAT6 和 IL-4 水平降低，这可能导致 PE 的发生。
