title: Role of epithelial Na+ channels in endothelial function.
abstract: An increasing number of mechano-sensitive ion channels in endothelial cells have been identified in response to blood flow and hydrostatic pressure. However, how these channels respond to flow under different physiological and pathological conditions remains unknown. Our results show that epithelial Na(+) channels (ENaCs) colocalize with hemeoxygenase-1 (HO-1) and hemeoxygenase-2 (HO-2) within the caveolae on the apical membrane of endothelial cells and are sensitive to stretch pressure and shear stress. ENaCs exhibited low levels of activity until their physiological environment was changed; in this case, the upregulation of HO-1, which in turn facilitated heme degradation and hence increased the carbon monoxide (CO) generation. CO potently increased the bioactivity of ENaCs, releasing the channel from inhibition. Endothelial cells responded to shear stress by increasing the Na(+) influx rate. Elevation of intracellular Na(+) concentration hampered the transportation of l-arginine, resulting in impaired nitric oxide (NO) generation. Our data suggest that ENaCs that are endogenous to human endothelial cells are mechano-sensitive. Persistent activation of ENaCs could inevitably lead to endothelium dysfunction and even vascular diseases such as atherosclerosis.
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China, 100871.
authors.forename: Dongqing
authors.initials: D
authors.lastname: Guo
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China, 100871.
authors.forename: Shenghui
authors.initials: S
authors.lastname: Liang
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China, 100871.
authors.forename: Su
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Cardiology, The School of Medicine, South East University, Nanjing, China, 210009.
authors.forename: Chengchun
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Cardiology, Nanjing General Hospital, Nanjing, China, 210000.
authors.forename: Bin
authors.initials: B
authors.lastname: Yao
authors.affiliation: Department of Cardiology, Nanjing General Hospital, Nanjing, China, 210000.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Wan
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, China, 050017.
authors.forename: Hailing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproduction, Department of Urology, Peking University Third Hospital, Beijing, China, 100191.
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Aston Medical School, Aston University, Birmingham, B4 7ET, UK.
authors.forename: Asif
authors.initials: A
authors.lastname: Ahmed
authors.affiliation: Department of Pharmacology, 2nd affiliated hospital of Harbin Medical University, Harbin, China, 150000 ycgu@pku.edu.cn zhangzr@yahoo.com.
authors.forename: Zhiren
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China, 100871 ycgu@pku.edu.cn zhangzr@yahoo.com.
authors.forename: Yuchun
authors.initials: Y
authors.lastname: Gu
mesh_terms: D026923:Amino Acid Transport Systems, Basic / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D002478:Cells, Cultured; D053503:Epithelial Sodium Channels / Q000502:physiology*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology*; D006801:Humans; D006874:Hydrostatic Pressure; D040542:Mechanotransduction, Cellular; D008564:Membrane Potentials; D009569:Nitric Oxide / Q000378:metabolism; D021381:Protein Transport
chemical_list: D026923:Amino Acid Transport Systems, Basic; D051242:Caveolin 1; D053503:Epithelial Sodium Channels; D009569:Nitric Oxide; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2
keywords: ENaC; Endothelium dysfunction; Heme; Mechanical stress; NO