Department of Obstetrics and Gynecology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake, Toyoake, Aichi 470-1192, Japan.
Placenta. 2012 Nov;33(11):919-26. doi: 10.1016/j.placenta.2012.08.003. Epub 2012 Sep 8.
High temperature requirement A (HtrA) family proteins are serine proteases that may serve in the quality control of misfolded or mislocalized proteins. Recently, possible involvements of HtrA1 in the normal development of the placenta and in the pathogenesis of pre-eclampsia were reported. In this study, we characterized HtrA4, a previously uncharacterized HtrA protein family member, in pre-eclampsia. Elevated expression levels of placental HtrA4 in pre-eclampsia patients were observed by qRT-PCR. Western blotting also showed an increased production of HtrA4 at the protein level in pre-eclamptic placentas. In normal chorionic villi, HtrA4 protein was more abundant in the cytoplasm of cytotrophoblasts than in syncytiotrophoblasts. In contrast, the amount of HtrA4 protein in syncytiotrophoblasts was dramatically increased in pre-eclamptic placentas. Circulating HtrA4 was detected at higher levels in sera from women with pre-eclampsia than from those with normotensive pregnancies. Serum HtrA4 levels were higher in patients with early onset and inversely correlated with the weights of the newborn and placenta. Furthermore, serum levels correlated with serum PAPP-A and PAPP-A2 levels, indicating a functional role for HtrA4 in the common pathway. These data suggest that increased HtrA4 may be involved in the onset of pre-eclampsia, and elevated levels in sera imply a potential application as a biomarker for this disorder.
高温需求 A（HtrA）家族蛋白是丝氨酸蛋白酶，可能参与错误折叠或定位错误的蛋白质的质量控制。最近，有报道称 HtrA1 可能参与胎盘的正常发育和子痫前期的发病机制。在这项研究中，我们对 HtrA4 进行了表征，HtrA4 是一种以前未被表征的 HtrA 蛋白家族成员，与子痫前期有关。qRT-PCR 观察到子痫前期患者胎盘 HtrA4 的表达水平升高。Western blot 也显示子痫前期胎盘的 HtrA4 蛋白水平增加。在正常绒毛膜绒毛中，HtrA4 蛋白在细胞滋养层细胞的细胞质中比在合体滋养层细胞中更为丰富。相比之下，子痫前期胎盘的合体滋养层细胞中 HtrA4 蛋白的量显著增加。与正常妊娠的妇女相比，子痫前期妇女的血清中检测到更高水平的循环 HtrA4。血清 HtrA4 水平在早发型患者中较高，与新生儿和胎盘的重量呈负相关。此外，血清水平与血清 PAPP-A 和 PAPP-A2 水平相关，表明 HtrA4 在共同途径中具有功能作用。这些数据表明，HtrA4 的增加可能与子痫前期的发生有关，而血清水平升高暗示其作为该疾病的生物标志物的潜在应用。
