title: Safrole oxide induces human umbilical vein endothelial cell transdifferentiation to 5-hydroxytryptaminergic neuron-like cells through tropomyosin receptor kinase A/cyclooxygenase 2/nuclear factor-kappa B/interleukin 8 signaling.
abstract: The phenomenon of endothelial-neural transdifferentiation has been observed for a long time, but the mechanism is not clear. We previously found that safrole oxide induced human umbilical vein endothelial cell transdifferentiation into neuron-like cells. In this study, we first validated that these cells induced by safrole oxide were functional 5-hydroxytryptaminergic neuron-like cells. Then, we performed microarray analysis of safrole oxide-treated and -untreated human umbilical vein endothelial cells. Safrole oxide elevated the levels of cyclooxygenase 2 (COX-2), interleukin-8 (IL-8) and reactive oxygen species (ROS), which was accompanied by nuclear factor-kappa B (NF-κB) nuclear translocation during the transdifferentiation. Blockade of tropomyosin receptor kinase A (TrkA) by an inhibitor or short hairpin RNA inhibited the levels of COX-2/IL-8 and the nuclear translocation of NF-κB but did not suppress the increased ROS level. As a result, cells underwent apoptosis. Therefore, via TrkA, safrole oxide may induce endothelial cell transdifferentiation into functional neuron-like cells. During this process, the increased levels of COX-2/IL-8 and the subsequent elevation of ROS production induced NF-κB nuclear translocation and IL-8 secretion. With the activity of TrkA inhibited, the inactive NF-κB regulated the ROS level in a negative feedback manner. Finally, the transdifferentiation pathway was blocked and cells became apoptotic. The TrkA/COX-2/IL-8 signal pathway may have an important role in endothelial-neural transdifferentiation, and safrole oxide may trigger this process by activating TrkA.
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, Institute of Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
authors.forename: Le
authors.initials: L
authors.lastname: Su
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Bao Xiang
authors.initials: BX
authors.lastname: Zhao
authors.forename: Shang Li
authors.initials: SL
authors.lastname: Zhang
authors.forename: Jun Ying
authors.initials: JY
authors.lastname: Miao
mesh_terms: D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival; D054338:Cell Transdifferentiation; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D020869:Gene Expression Profiling; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012451:Safrole / Q000031:analogs & derivatives* / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*; D014335:Tropomyosin / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects
chemical_list: D016209:Interleukin-8; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014335:Tropomyosin; D012701:Serotonin; C009196:safrole oxide; D051546:Cyclooxygenase 2; D011494:Protein Kinases; C041311:tropomyosin kinase; D012451:Safrole; D002118:Calcium