title: Clinorotation upregulates inducible nitric oxide synthase by inhibiting AP-1 activation in human umbilical vein endothelial cells.
abstract: Alterations of nitric oxide contribute to post-flight orthostatic intolerance. The aim of this study was to investigate the changes of inducible nitric oxide synthase (iNOS) and the mechanisms underlying regulation of iNOS by simulated microgravity in human umbilical vein endothelial cells (HUVECs). Clinorotation, a simulated-model of microgravity, increased iNOS expression and promoter activity in HUVECs. The transactivations of NF-kappaB and AP-1 were suppressed by 24 h clinorotation. A key role for AP-1, but not NF-kappaB in the regulation of iNOS was shown. (1) PDTC, a NF-kappaB inhibitor, had no effect on clinorotation upregulation of iNOS. (2) SP600125, a JNK-specific inhibitor, which resulted in inhibition of AP-1 activity, enhanced the iNOS expression and promoter activity in clinorotation. (3) Overexpression of AP-1 remarkably attenuated the upregulation effect of clinorotation. These findings indicate that clinorotation upregulates iNOS in HUVECs by a mechanism dependent on suppression of AP-1, but not NF-kappaB. These results support a key role for AP-1 in the signaling of postflight orthostatic intolerance.
authors.affiliation: Department of Aerospace Biodynamics, Fourth Military Medical University, Xi'an, China.
authors.forename: Yong-Chun
authors.initials: YC
authors.lastname: Wang
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
authors.forename: Ting-Yuan
authors.initials: TY
authors.lastname: Du
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Xi-Qing
authors.initials: XQ
authors.lastname: Sun
mesh_terms: D015153:Blotting, Western; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000235:genetics; D054971:Orthostatic Intolerance / Q000503:physiopathology*; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012399:Rotation / Q000009:adverse effects*; D013026:Space Flight; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation; D014471:Umbilical Veins; D015854:Up-Regulation; D018474:Weightlessness Simulation
chemical_list: D016328:NF-kappa B; D018808:Transcription Factor AP-1; D052247:Nitric Oxide Synthase Type II