Expressional and Epigenetic Alterations of Placental Serine Protease Inhibitors

Abstract

Abstract-Preeclampsia is the major pregnancy-induced hypertensive disorder. It modifies the expression profile of placental genes, including several serine protease inhibitors (SERPINs). The objective of this study was to perform a systematic expression analysis of these genes in normal and pathological placentas and to pinpoint epigenetic alterations inside their promoter regions. Expression of 18 placental SERPINs was analyzed by quantitative RT-PCR on placentas from pregnancies complicated by preeclampsia, intrauterine growth restriction, or both and was compared with normal controls. SERPINA3, A5, A8, B2, B5, and B7 presented significant differences in expression in Ն1 pathological situation. In parallel, the methylation status of the CpG islands located in their promoter regions was studied on a sample of control and preeclamptic placentas. Ten SERPIN promoters were either totally methylated or totally unmethylated, whereas SERPINA3, A5, and A8 presented complex methylation profiles. For SERPINA3, the analysis was extended to 81 samples and performed by pyrosequencing. For the SERPINA3 CpG island, the average methylation level was significantly diminished in preeclampsia and growth restriction. The hypomethylated CpGs were situated at putative binding sites for developmental and stress response (hypoxia and inflammation) factors. Our results provide one of the first observations of a specific epigenetic alteration in human placental diseases and provide new potential markers for an early diagnosis.

Prevention of gravidic endothelial hypertension by aspirin treatment administered from the 8th week of gestation

“…Indeed, specific alterations of protein content in the mother's serum in pre-eclampsia have now been documented in several proteomic studies. 7,8 Pro-inflammatory molecules such as C-reactive protein were consistently increased in the maternal serum along with coagulation factors such as gamma fibrinogen, various SERPINs of the A and C clades (some possibly synthesized by the placenta) 9 and lipid transport molecules such as apolipoproteins.…”

DNA methylation profiling of human placentas reveals promoter hypomethylation of multiple genes in early-onset preeclampsia

“…SERPINA3, another gene in the SERPIN family, has been reported to be hypomethylated in severe preeclampsia, but the extent of methylation and its potential for being a clinical marker have not been examined thoroughly. 8 We suggest, therefore, that the level of unmethylated TIMP3 DNA in maternal plasma could be a useful biomarker for early detection of severe preeclampsia. In summary, we report the application of DNA methylation analysis to the elucidation of abnormal placental development associated with preeclampsia.…”

“…Epigenetic alterations of non-imprinted genes have also been suggested to be involved. For example, the SERPINA3 promoter was found to be hypomethylated in preeclampsia-associated placenta, 8 suggesting that the epigenetic alteration of this gene may be associated with reduced trophoblastic invasion and implicating this change as a potential biomarker for preeclampsia.…”

Detection of global DNA methylation and paternally imprinted H19 gene methylation in preeclamptic placentas

“…Results from two independent laboratories demonstrated that significant hypomethylation occurs in the promoter regions of the serpinb5 and serpina3 genes in preeclamptic placenta as compared with normal controls placentas. 10,11 Novakovic et al reported decreased DNA methylation levels of the cyp24a1 gene in preeclamptic placenta tissues. 12 However, most of these evidences are limited to the analysis of individual genes, and variations of global DNA methylation is still poorly understood in PE.…”