The Molecular Mechanism And Prediction Of Preeclampsia

Hypertensive disorders complicating pregnancy (HDCP) is one of the complications during pregnancy with high incidence and mortality, which threatens health and safety of mother and baby.The preeclampsia (PE) is a typical case of HDCP and a kind of placenta-derived disease with various pathological physiology changes which result from systemic small vasospasm and hypoxia, oxidative damage and necrosis occur in the placenta.Oxidative stress in placenta maternal-fetal interface may lead to the change of the body’s immune response, and then induces cells injury in vascular endothelial and renal damage. The changes of expressions of cyclooxygenase-2(COX-2), tumor necrosis factor-a (TNF-a) are related to inflammatory reaction. Thioredoxin-1(TRX-1) is a redox regulatory protein, and is expressed in placental cytotrophoblast, decidua and stromal cells. TRX-1has been shown to play crucial roles in scavenging reactive oxygen species (ROS) and enhancing cell proliferation and inhibiting apoptosis and regulating inflammation. Thioredoxin-1binding protein-2(TBP-2) is the endogenous inhibitor of TRX-1and inhibits TRX-1activity. TBP-2plays the roles in regulating inflammation and apoptosis. However, whether the TBP-2is involved in the pathogenic process of PE has not been reported.Both inhibin and activin belong to Transforming Growth Factor-beta (TGF-beta) family, in which activin A is composed of2beta A subunit; while according to the chain of alpha and beta chain composed subtypes, inhibin are divided into inhibin-A and inhibin-B. The physiological functions of activin and inhibin are different. Inhibin could combine with activin receptors and inhibit the signal transduction of activin. They work together to regulate counts and immersion of placental trophoblastic cells, embryo implantation and differentiation. The expression level gradually increases with the increased pregnancy gestational age. PE is implicated with abnormal levels of activin and inhibin, however, its molecular mechanism is still unknown.Pregnancy-associated plasma protein-A (PAPP-A) is a macromolecule glycoprotein produced by placental syncytiotrophoblast and reflect the function of syncytiotrophoblast. Studies have shown that the concentration of PAPP-A in the maternal blood increased in the early stages of PE, and its expression level was directly related to the diastolic blood pressure. Thus, the concentration of PAPP-A in the maternal blood was used to analyze the risk of PE.In addition, many studies have shown that patients with PE usually are complicated with abnormal lipid metabolism, which triggers different levels of vascular endothelial cell damage and leads to increase of vascular permeability and cholesterol deposition in the vessel, causes vascular lesions, hypertension and urinary protein.In this study, enzyme-linked immunosorbent assay (ELISA) was used to detect the level of Inhibin-A and rverse transcrip-tion-polymerase chain reaction (RT-PCR) was used to detect mRNA expression levels of Inhibin-A^Activin-A and Inhibin-B subunit gene. The mRNA expression levels of TRX-1, TBP-2, inflammatory factor COX-2and TNF-alpha in placenta were quantified by fluorescent real PCR. In addition, we detected the levels of each component in blood lipid plasma, including total cholesterol (TG), Triglycerides (TC), high-density lipoprotein (HDL), low density lipoprotein (LDL), apolipoprotein Apo-A, Apo B, Lp (a), serum free fatty acid (FFA) in patients with PE, to confirmed the correlation between PE with abnormal lipid metabolism and lipid components change. Finally, we detected the level of PAPP-A in serum and mRNA level of PAPP-A in placenta and analyzed correlation of the level of PAPP-A of pregnant women between PE and normal group and try to find the way to predict PE.The results in this paper as below:(1) The results showed that the level of Inhibin-A in serum of PE was significantly higher than normal pregnant women, suggesting the level of Inhibin-A in serum is related with PE. In addcition, level of Inhibin-A was increased three times compared normal group in placenta. However, Inhibin-B in placenta of PE and normal pregnant women had no significant difference. As the pathological changes of PE induced the placenta damage, we speculated that subunit gene expression changes of Inhibin/Activin may be related to the increased in placenta of PE under the stimulation.(2) The realtime fluorescence quantitative PCR was used to detect the TRX-1and TBP-2expressions in placenta tissues. The TRX-1mRNA expression level in placenta of pre-eclampsia was lower than the normal group, while TBP-2mRNA expression significantly was increased in preeclampsia compared to normal group. In order to further confirm whether there was inflammation in preeclampsia, we detected the expressions of TNF-a and COX-2in placenta of preeclampsia. The results showed that the levels of TNF-a and COX-2in placenta of preeclampsia group were significantly higher than control group.(3) The triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL), apolipoprotein Lp (a), ApoB, free fatty acid (FAA) were increased, while ApoAl and HDL were decreased in serum of mild and severe preeclampsia patients, respectively. Therefore, lipid metabolism disorder is associated with PE.(4) The level of PAPP-A in serum of nomal pregnant women was positively correlated with gestational weeks. With the increase of gestational weeks, the level of PAPP-A was increased. The midian value of PAPP-A in serum of different gestational weeks were found in normal group. The level of PAPP-A in serum of early and middle PE was significantly higher than control group. The mRNA expression level of PAPP-A in placenta of preeclampsia significantly increased. The statistical methods and ROC curve were used to analyze the predictive value of PAPP-A in PE. The results were as follows:(1) the area under the ROC curve was0.837(p<0.01);(2) The sensitivity was73.8%and the false positive rate was17.3%when the PAPP-A cutoff value was1.84MOM;(3) The sensitivity was70.1%and the false positive rate was14.4%when the PAPP-A cutoff value was2.0MOM;(4) The sensitivity was57.8%and the false positive rate was10.4%when cutoff value was2.28MOM.The above results showed that the level of Inhibin-A in serum of patients with preeclampsia was significantly higher than normal pregnant women. The mRNA expression levels of Inhibin A and Activin-A in preeclampsia women were higher than normal pregnant women. The abnormal expressions of Inhibin-A and Activin-A were associated with PE. The decrease of Trx-1and the increase of TBP-2may be involved in oxidative stress and inflammation in preeclampsia, and the TRX-1and TBP-2are treatment targets for the preeclampsia. The abnormal lipid metabolism occurred obviously in preeclampsia patients. Lipid metabolic abnormalities are associated with the development of the preeclampsia. The MoM values of PAPP-A in serum of early and mid-phase of PE pregnant women were increased significantly compared with normal pregnant women, thus, PAPP-A could be a maker of diagnosis for early and mid-phase of PE.