Functional proteomics of neurokinin B in the placenta indicates a novel role in regulating cytotrophoblast antioxidant defences.
Neurokinin B (NKB) has recently been demonstrated to be secreted from the placenta in abnormally high amounts in preeclampsia (PE) and to cause hypertension in rats, suggesting it may be a mediator of some pathophysiological features of PE. It is also known that NKB receptors exist in the placenta. To determine the effect of high levels of NKB on the placenta, we have performed proteomics on five separate preparations of cultured purified human term cytotrophoblast cells. The results showed a statistically significant decrease in 20 proteins, of which five were unknown proteins. Proteins important in antioxidant defenses that decreased were thioredoxin, cyclophilin A, cytokeratin 1, and peroxiredoxin 5. Two proteins that inhibit intravascular anticoagulation, cytokeratin 1 and annexin 11 were also decreased. Pathways involving pro-inflammatory cytokine activation of NF-kappa B are opposed by Raf kinase inhibitor protein, which was also decreased. Cofilin 1, a protein involved in defense against bacteria, was also decreased. Among other proteins that were suppressed by NKB were proteasome proteins, desmoplakin, and calgizzarin. Western blots confirmed the decrease in cytokeratin 1 and cyclophilin A protein after NKB exposure. In PE, there is reduced antioxidant activity and increased intravascular coagulation. The findings that high levels of NKB, similar to those observed in PE, can impair these two classes of activity support the hypothesis that high NKB levels may contribute to the pathogenesis of PE.
Sawicki
Grzegorz
G
Department of Pharmacology, Cardiovascular Research Group, University of Alberta, Edmonton, Canada.
Dakour
Jamal
J
Morrish
Donald W
DW
D017302:Annexins / Q000032:analysis / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D021984:Cyclophilin A / Q000032:analysis / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000378:metabolism; D051180:Desmoplakins; D015536:Down-Regulation; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007633:Keratins / Q000032:analysis / Q000378:metabolism; D015287:Neurokinin B / Q000494:pharmacology*; D010544:Peroxidases / Q000032:analysis / Q000378:metabolism; D054464:Peroxiredoxins; D010920:Placenta / Q000737:chemistry* / Q000166:cytology / Q000378:metabolism; D011225:Pre-Eclampsia / Q000378:metabolism / Q000503:physiopathology; D011247:Pregnancy; D020543:Proteome / Q000032:analysis*; D040901:Proteomics / Q000379:methods*; D009418:S100 Proteins / Q000032:analysis / Q000378:metabolism; D013879:Thioredoxins / Q000032:analysis / Q000378:metabolism; D014327:Trophoblasts / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism
D017302:Annexins; D000975:Antioxidants; D003598:Cytoskeletal Proteins; C495294:DSP protein, human; D051180:Desmoplakins; D020543:Proteome; D009418:S100 Proteins; C072337:S100A11 protein, human; D013879:Thioredoxins; D007633:Keratins; D015287:Neurokinin B; D010544:Peroxidases; C515974:PRDX5 protein, human; D054464:Peroxiredoxins; D021984:Cyclophilin A