The Role Of Ferroptosis In Preeclampsia And Its Mechanism

BackgroundPreeclampsia is a syndrome that occurs after 20 weeks of pregnancy and is characterized by high blood pressure and damage to various organs,including the heart,brain and kidney.Globally,preeclampsia is a significant contributor to maternal mortality.The etiology of preeclampsia has not been elucidated,and this has led to limited treatment and prevention options for preeclampsia.Ferroptosis is a newly discovered form of programmed cell death that is triggered by the accumulation of iron and lipid peroxides in cells,and involves complex signaling pathways regulating iron metabolism,lipid peroxidation and antioxidant defense.Previously we found that GPR124 plays an important role in preeclampsia,and GPR124 is related to ferroptosis.Further studies are needed to fully understand the role of ferroptosis in preeclampsia and whether GPR124 plays a role in this process.MethodsThis is a research study that includes women who gave birth in the obstetrics department of the Shenzhen Maternity and Child Healthcare Hospital affiliated with Southern Medical University between January 2017 and December 2020(singleton)as the research subjects for a case-control study.The propensity matching method was used to match the baseline characteristic distribution differences between the balanced pre-eclampsia group and the normal control group.T-test,Mann-Whitney U test,chi-square test and Fisher’s exact test were used to compare the differences in baseline data and biochemical indicators such as serum ferritin between the two groups.Pearson correlation analysis was used to study the correlation between serum ferritin and clinical data and biochemical indicators.qPCR,Western blot and immunohistochemical staining were used to detect the expression of iron death-related molecules(TFRC,FSP1 and GPX4)in the placenta.HPA database analysis was used to analyze the expression of GPR124 in human tissues and cells.Immunofluorescence was used to detect the expression and localization of GPR124 in the placenta.HUVEC cells were used for GPR124 overexpression and knockdown cell model studies.CCK8 was used to detect cell proliferation ability.The colorimetric method was used to detect total iron and ferrous levels in cells.The TBA method was used to detect the level of lipid peroxide(MDA)in cells.The total glutathione and oxidized glutathione content were measured to calculate the reduced glutathione(GSH)content.The DCFH-DA probe was used to detect the level of reactive oxygen species(ROS)in cells.qPCR and Western blot were used to detect the expression of ferroptsis related molecules in cells.ResultsThe study found that serum ferritin levels were significantly higher in women with preeclampsia(31.20±2.141ng/ml)compared to the normal control group(22.75±1.58 ng/ml),and a higher proportion of preeclampsia women had sufficient iron levels(82.68%vs 73.18%).There were positive correlations between serum ferritin levels and RBC,PLT,ALB,T PROT and diastolic blood pressure(P<0.05).The proportion of iron sufficient parturients in preeclampsia group was 82.68%,which was higher than that in normal controls(73.18%),and the difference was statistically significant(P<0.05).Compared with the normal control group,Placentas from preeclampsia group showed down-regulation of FSP1 and GPX4,while no difference was observed in TFRC expression.GPR124 was found to be co-localized with CD31 in the placental blood vessels.Knockdown of GPR124 in umbilical vein endothelial cells(HUVECs)promoted ferroptosis,while overexpression of GPR124 inhibited iron death.The ferroptosis represented as reduced cell proliferation,increased levels of total and ferrous iron,elevated levels of lipid peroxide(MDA)levels and ROS levels,decreased levels of reduced GSH,upregulation of transferrin receptor(TFRC),and downregulation of FSP1 and GPX4.ConclusionsIncreased serum ferritin levels in pregnant women with preeclampsia suggests that inflammation and iron metabolism imbalance are involved in preeclampsia.The expression of ferroptosis key molecules(TFRC,FSP1 and GPX4)in the placenta confirms that ferroptosis is related to the pathogenesis of preeclampsia.The occurrence of ferroptosis in placental vascular endothelium cells is regulated by GPR124.