1. Trimethylamine N-Oxide increases soluble fms-like tyrosine Kinase-1 in human placenta via NADPH oxidase dependent ROS accumulation
- Author
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Nailiang Zang, Laixin Xia, Ming-xin Yang, Mei Zhong, Qing-xian Chang, Nanbert Zhong, Le-qian Li, Xia Chen, and Qi-tao Huang
- Subjects
0301 basic medicine ,Placenta ,Trimethylamine N-oxide ,Methylamines ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pre-Eclampsia ,Pregnancy ,Dichlorofluorescein ,Humans ,Secretion ,Cells, Cultured ,Vascular Endothelial Growth Factor Receptor-1 ,030219 obstetrics & reproductive medicine ,NADPH oxidase ,biology ,NADPH Oxidases ,Obstetrics and Gynecology ,Trophoblasts ,Cell biology ,030104 developmental biology ,Gene Expression Regulation ,Reproductive Medicine ,chemistry ,Cell culture ,embryonic structures ,Apocynin ,biology.protein ,Female ,Reactive Oxygen Species ,Oxidation-Reduction ,Tyrosine kinase ,Soluble fms-like tyrosine kinase-1 ,Developmental Biology - Abstract
Backgrounds Preeclampsia (PE) is characterized as placental vascular disturbance and excessive secretion of soluble fms-like tyrosine kinase 1 (sFlt-1) into the maternal circulation. Trimethylamine N-oxide (TMAO, a gut microbe-derived metabolite) is strongly associated with various cardiovascular and cerebrovascular diseases. Recently, we observe that higher maternal circulating TMAO and sFlt-1 in patients with PE. The aims of the present study are to explore the effects of TMAO on placental sFlt-1 production and the underlying mechanism in human placenta. Methods Human placental explants, human placental primary trophoblasts and the extravillous trophoblasts (EVT) cell line (HRT-8/SVneo) were exposured to various concentrations of TMAO (100, 150, 300, and 600 μM). The mRNA expression and protein secretion of sFlt-1 in placental explants, primary trophoblasts and HRT-8/SVneo cells were determined with qPCR and ELISA, respectively. The levels of intracellular reactive oxygen species (ROS) production in primary trophoblasts and HRT-8/SVneo cells were measured by peroxide-sensitive fluorescent probe dichlorofluorescein diacetate. Results Exposure of placental explants, primary trophoblasts and HRT-8/SVneo cells to TMAO significantly enhanced sFlt-1 at both mRNA and protein levels in a dose dependent manner. Moreover, inhibition of NADPH oxidase with apocynin significantly attenuated TMAO-induced ROS production in primary trophoblasts and HRT-8/SVneo, and suppressed sFlt-1 secretion in placental explants, primary trophoblasts and HRT-8/SVneo. Conclusions Our findings indicated the NADPH oxidase dependent ROS pathway played a critical role in mediating TMAO-induced sFlt-1 generation in human placenta. TMAO may become a potential novel target for pharmacological or dietary interventions to reduce the risk of developing PE.
- Published
- 2021