他汀类药物通过miR-155改善子痫前期小鼠血管内皮功能障碍的机制研究

Preeclampsia (PE) is a severe pregnancy complication. Currently there is still no effective medicine for the prevention or treatment of this disease. Using animal models of PE, it has been demonstrated that statins may prevent the development of PE in mice via improving their endothelial functions. As statins are contraindicated in human pregnancy, it is not permitted to use them in pregnant women. Therefore, it is necessary to study the key molecules responsible for the efficacy of statins. We have found microRNA-155 (miR-155) is over-expressed in PE, which may prevent normal vasodilatation through inhibiting eNOS expression. Meanwhile, statins inhibit the expression of miR-155, thereby reinstating the expression of eNOS and vasodilatation. Our findings indicate that miR-155 may act as an important molecule in the improvement of endothelial functions by statins. In addition, injection of anti-miR-155 into PE mice significantly reduces circulating miR-155 from the placentas and ameliorates the hypertension and proteinuria of PE mice. Therefore, we hypothesize that miR-155 may be the key molecule in regulating endothelial functions of PE, and secretory miR155 from placental exosomes involves in impairing endothelial functions in PE. Based on miR-155 transgenic animal models, miR-155 KO mice and PE animal models, combined with in vitro experiments, we aim to investigate the mechanism in the improvement of endothelial functions by statins and the role of secretory miRNAs in PE, and search for new targets in treatment for PE.

子痫前期（PE）是严重妊娠并发症，尚无有效防治药物。动物模型中他汀通过改善血管内皮功能减轻PE表型。但他汀是妊娠期X类药，暂难用于临床。因此需从其作用途径中寻找关键分子。我们已证明miR-155对胎盘和外周血管有重要调控作用，其表达异常与PE相关；miR-155靶向抑制内皮一氧化氮合酶（eNOS），干扰血管舒张。而他汀可抑制miR-155，恢复eNOS水平及血管舒张功能，提示miR-155是他汀改善PE血管功能的重要媒介。我们发现PE小鼠胎盘通过外泌体分泌大量miR-155；而反义miR-155能降低胎盘外泌体中miR-155，改善高血压、蛋白尿表型。综上设想：miR-155是调控PE血管内皮功能的关键分子；胎盘通过分泌miR-155调控外周血管功能。本研究拟借助miR-155基因工程动物及PE模型，结合体外实验研究他汀改善血管内皮功能的机制及分泌型miRNA在PE发病中的作用。

子痫前期（PE）是严重妊娠并发症，尚无有效防治药物。本研究以滋养细胞和LPS诱导的PE大鼠为模型，结合临床调查，探讨普伐他汀及姜黄素治疗PE大鼠的分子机制。我们做了以下工作：1、明确了miR-155、eNOS等关键分子在PE患者及动物模型中的表达情况；2、发现PE胎盘分泌的外泌体表达miR-155增加，并损伤血管内皮功能；3、发现miR-155可通过调控血管内皮细胞中eNOS蛋白的乙酰化修饰来抑制eNOS的表达；4、建立了血管内皮特异性高表达miR-155大鼠模型，并分析了其对妊娠的影响；5、研究了普伐他汀改善LPS引起的滋养细胞功能抑制及PE大鼠表型的分子机制；6、动物模型评价了普伐他汀对胎儿的安全性；7、研究了姜黄素改善LPS引起的滋养细胞功能抑制及PE大鼠表型的分子机制；8、成功建立了胎盘特异性表达miR-155转基因小鼠，并对PE表型进行了初步鉴定。以上结果表明，PE患者不仅胎盘表达miR155增加，而且miR-155可通过外泌体影响血管内皮细胞eNOS表达，导致NO产生减少，血管收缩功能增强。这种调控异常是PE发病的重要机制之一，而普伐他汀及姜黄素通过TLR4信号通路抑制miR-155的表达从而达到治疗PE的效果。