title: NADPH oxidase 2-derived superoxide downregulates endothelial KCa3.1 in preeclampsia.
abstract: Endothelial dysfunction is associated with KCa3.1 dysfunction and contributes to the development of hypertension in preeclampsia. However, evidence of endothelial KCa3.1 dysfunction in the vascular system from women with preeclampsia is still lacking. Therefore, we examined whether endothelial KCa3.1 dysfunction occurs in vessels from women with preeclampsia. We compared KCa3.1 and NADPH oxidase (NOX) expression in umbilical vessels and primary cultured human umbilical vein endothelial cells (HUVECs) from normal (NP; n=17) and preeclamptic pregnancy (PE; n=19) and examined the effects of plasma from NP or PE on KCa3.1 and NOX2 expression in primary cultured HUVECs from NP or human uterine microvascular endothelial cells. The endothelial KCa3.1 was downregulated, and NOX2 was upregulated, in umbilical vessels and HUVECs from PE, compared with those from NP. In addition, HUVECs from PE showed a significant decrease in KCa3.1 current. Plasma from PE induced KCa3.1 down regulation, NOX2 upregulation, phosphorylated-p38 mitogen-activated protein kinase downregulation, and superoxide generation, and these effects were prevented by antioxidants (tempol or tiron), NOX2 inhibition, or anti-lectin-like oxidized low-density lipoprotein (LDL) receptor 1 (LOX1) antibody. Oxidized LDL and the superoxide donor xanthine/xanthine oxidase mixture induced KCa3.1 downregulation. In contrast, plasma from PE did not generate hydrogen peroxide, and the hydrogen peroxide donor tert-butylhydroperoxide induced KCa3.1 upregulation. These results provide the first evidence that plasma from PE generates superoxide via a LOX1-NOX2-mediated pathway and downregulates endothelial KCa3.1, which may contribute to endothelial dysfunction and vasculopathy in preeclampsia. This suggests KCa3.1as a novel target for patients with preeclampsia.
authors.affiliation: Department of Physiology Medical School, Ewha Womans University, Seoul 158-710, Republic of Korea.
authors.forename: Shinkyu
authors.initials: S
authors.lastname: Choi
authors.forename: Ji Aee
authors.initials: JA
authors.lastname: Kim
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Na
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Seonghee
authors.initials: S
authors.lastname: Park
authors.forename: Ki-Hwan
authors.initials: KH
authors.lastname: Han
authors.forename: Young Ju
authors.initials: YJ
authors.lastname: Kim
authors.forename: Suk Hyo
authors.initials: SH
authors.lastname: Suh
mesh_terms: D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007202:Indicators and Reagents / Q000494:pharmacology; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D011225:Pre-Eclampsia / Q000097:blood / Q000378:metabolism*; D011247:Pregnancy; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E / Q000276:immunology / Q000378:metabolism*; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism*; D014471:Umbilical Veins / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020122:tert-Butylhydroperoxide / Q000378:metabolism
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D007202:Indicators and Reagents; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D008562:Membrane Glycoproteins; C495137:OLR1 protein, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; D013113:Spin Labels; D013481:Superoxides; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D020122:tert-Butylhydroperoxide; D006861:Hydrogen Peroxide; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases; C001803:tempol