Clinorotation upregulates inducible nitric oxide synthase by inhibiting AP-1 activation in human umbilical vein endothelial cells.
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.
Wang
Yong-Chun
YC
Department of Aerospace Biodynamics, Fourth Military Medical University, Xi'an, China.
Zhang
Shu
S
Du
Ting-Yuan
TY
Wang
Bing
B
Sun
Xi-Qing
XQ
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
D016328:NF-kappa B; D018808:Transcription Factor AP-1; D052247:Nitric Oxide Synthase Type II