Nuclear factor of activated T-cells (NFAT) regulates soluble fms-like tyrosine kinase-1 secretion (sFlt-1) from human placenta

作者：Ye Louie; Gratton Amy; Hannan Natalie J; Cannon Ping; Deo Minh; Palmer Kirsten R; Tong Stephen; Kaitu' u Lino Tu' uhevaha J; Brownfoot Fiona C

来源：Placenta, 2016, 48: 110-118.

DOI：10.1016/j.placenta.2016.10.013

• Preeclampsia
• NFAT
• sFlt-1
• Hypoxia

Introduction: Preeclampsia is a serious complication affecting 5-8% of pregnancies. Central to its pathogenesis is placental hypoxia and inflammation which leads to secretion of soluble fms-like tyrosine kinase 1 (sFlt-1). sFlt-1 causes widespread endothelial dysfunction. The molecular mechanisms regulating sFlt-1 production remain poorly understood. Recently, a binding site for the nuclear factor activated T cells (NFAT) transcription factor has been found on fms-like tyrosine kinase 1 (FLT-1) promoter.
Methods: We assessed whether inhibiting NFAT impacts FLT-1, sFlt-1 and cytokine expression, as well as sFlt-1 secretion in primary cytotrophoblasts, placental explants and human umbilical vein endothelial cells (HUVECs). We investigated whether NFAT is regulated by hypoxia in primary cytotrophoblasts. We characterised the expression of NFAT1-4 in preterm preeclamptic compared to gestationally matched placentas.
Results: Inhibiting NFAT reduced FLT-1 and sFlt-1 splice variant el5a transcription, concordant with reduced total sFlt-1 and sFlt-1 el5a secretion from primary human cytotrophoblasts. This effect appeared tissue specific as inhibiting NFAT did not change sFlt-1 secretion from endothelial cells. Inhibiting NFAT also reduced transcription of inflammatory cytokines IL-1 beta and IL-10 in primary cytotrophoblasts. NFAT1 and NFAT3 mRNA expression were significantly increased under hypoxia (1% O-2). Inhibiting NFAT under hypoxia significantly reduced FLT-1 and sFlt-1 el5a transcription, but did not reduce sFlt-1 secretion. NFAT mRNA and protein localisation was not different in preeclamptic compared to gestationally matched placenta.
Discussion: NFAT positively regulates placental FLT-1 and sFlt-1 e15a, secretion of sFlt-1 and inflammatory cytokine expression. It may be involved in the pathophysiology of preeclampsia.

• 出版日期2016-12