Low-dose aspirin reduces hypoxia-induced sFlt1 release via the JNK/AP-1 pathway in human trophoblast and endothelial cells.
Pre-eclampsia (PE) is a serious hypertensive disorder of pregnancy that remains a leading cause of perinatal and maternal morbidity and mortality worldwide. Placental ischemia/hypoxia and the secretion of soluble fms-like tyrosine kinase 1 (sFlt1) into maternal circulation are involved in the pathogenesis of PE. Although low-dose aspirin (LDA) has beneficial effects on the prevention of PE, the exact mechanisms of action of LDA, particularly on placental dysfunction, and sFlt1 release, have not been well investigated. This study aimed to determine whether LDA exists the protective effects on placental trophoblast and endothelial functions and prevents PE-associated sFlt1 release. First, we observed that LDA mitigated hypoxia-induced trophoblast apoptosis, showed positive effects on trophoblast cells migration and invasion activity, and increased the tube-forming activity of human umbilical vein endothelial cells (HUVECs). In addition, LDA decreased hypoxia-induced sFlt1 production, and the c-Jun NH2 -terminal kinase/activator protein-1 (JNK/AP-1) pathway was shown to mediate the induction of sFlt1. Moreover, the transcription factor AP-1 was confirmed to regulate the Flt1 gene expression by directly binding to the Flt1 promoter in luciferase assays. The result of chromatin immunoprecipitation assays further demonstrated that LDA could directly decrease the expression of the transcription factor AP-1, and thus decrease sFlt1 production. Finally, the effects of LDA on sFlt1 production were proved in human placental explants. Taken together, our data show the protective effects of LDA against trophoblast and endothelial cell dysfunction and reveal that the LDA-mediated inhibition of sFlt1 via the JNK/AP-1 pathway may be a potential cellular/molecular mechanism for the prevention of PE.
['Lin|Li|L|0000-0002-4117-2314', 'Li|Guanlin|G|', 'Zhang|Wanyi|W|', 'Wang|Yan-Ling|YL|', 'Yang|Huixia|H|']
D000328:Adult D000894:Anti-Inflammatory Agents, Non-Steroidal D017209:Apoptosis D001241:Aspirin D015687:Cell Hypoxia D002460:Cell Line D002465:Cell Movement D005260:Female D061307:Human Umbilical Vein Endothelial Cells D006801:Humans D048031:JNK Mitogen-Activated Protein Kinases D020935:MAP Kinase Signaling System D010920:Placenta D011225:Pre-Eclampsia D011247:Pregnancy D018808:Transcription Factor AP-1 D014327:Trophoblasts D040281:Vascular Endothelial Growth Factor Receptor-1
aspirin pre-eclampsia (PE) hypoxia soluble fms-like tyrosine kinase 1 (sFlt1) c-Jun NH2-terminal kinase/activator protein-1 (JNK/AP-1) pathway