Trimethylamine N-Oxide increases soluble fms-like tyrosine Kinase-1 in human placenta via NADPH oxidase dependent ROS accumulation. (1st January 2021)

• Record Type: Journal Article
• Authors: Chang, Qing-xian; Chen, Xia; Ming-xin Yang, ; Zang, Nai-liang; Li, Le-qian; Zhong, Nanbert; Xia, Lai-xin; Huang, Qi-tao; Zhong, Mei
• Is Part Of: Placenta. Volume 103(2021)
• Page Start: 134
• Page End: 140
• Publication Date: 2021-01-01
• Subjects: Trimethylamine-N-oxide -- Preeclampsia -- Soluble fms-like tyrosine kinase 1; Placenta -- Periodicals; Reproduction -- Periodicals; Placenta -- Periodicals; Placenta -- Périodiques; Reproduction -- Périodiques; 612.63
• DOI: 10.1016/j.placenta.2020.10.021
• Languages: English
• ISSNs: 0143-4004

Abstract

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. Highlights: TMAO promotes sFlt-1 production in placental trophoblasts and explants. TMAO significantly enhanced ROS generation in placental trophoblasts and explants. Inhibition of NADPH Oxidase attenuated TMAO-mediated sFlt-1 production.