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      Zinc regulates vascular endothelial cell activity through zinc-sensing receptor ZnR/GPR39


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          Zn 2+ is an essential element for cell survival/growth, and its deficiency is linked to many disorders. Extracellular Zn 2+ concentration changes participate in modulating fundamental cellular processes such as proliferation, secretion, ion transport, and cell signal transduction in a mechanism that is not well understood. Here, we hypothesize that the Zn 2+-sensing receptor ZnR/G protein-coupled receptor 39 (GPR39), found in tissues where dynamic Zn 2+ homeostasis takes place, enables extracellular Zn 2+ to trigger intracellular signaling pathways regulating key cell functions in vascular cells. Thus, we investigated how extracellular Zn 2+ regulates cell viability, proliferation, motility, angiogenesis, vascular tone, and inflammation through ZnR/GPR39 in endothelial cells. Knockdown of GPR39 through siRNA largely abolished Zn 2+-triggered cellular activity changes, Ca 2+ responses, as well as the downstream activation of Gαq-PLC pathways. Extracellular Zn 2+ promoted vascular cell survival/growth through activation of cAMP and Akt as well as overexpressing of platelet-derived growth factor-α receptor and vascular endothelial growth factor A. It also enhanced cell adhesion and mobility, endothelial tubule formation, and cytoskeletal reorganization. Such effects from extracellular Zn 2+ were not observed in GPR39 −/− endothelial cells. Zn 2+ also regulated inflammation-related key molecules such as heme oxygenase-1, selectin L, IL-10, and platelet endothelial cell adhesion molecule 1, as well as vascular tone-related prostaglandin I2 synthase and nitric oxide synthase-3. In sum, extracellular Zn 2+ regulates endothelial cell activity in a ZnR/GPR39-dependent manner and through the downstream G αq-PLC pathways. Thus, ZnR/GPR39 may be a therapeutic target for regulating endothelial activity.

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          Author and article information

          Am J Physiol Cell Physiol
          Am. J. Physiol., Cell Physiol
          Am J Physiol Cell Physiol
          American Journal of Physiology - Cell Physiology
          American Physiological Society (Bethesda, MD )
          1 April 2018
          13 December 2017
          1 April 2019
          : 314
          : 4
          : C404-C414
          [1] 1Department of Biomedical Engineering, University of North Texas , Denton, Texas
          [2] 2Department of Materials Science and Engineering, College of Engineering, Peking University , Beijing, China
          [3] 3Department of Biomedical Engineering, The City College of the City University of New York , New York, New York
          [4] 4Department of Bioengineering, University of Texas at Arlington , Arlington, Texas
          [5] 5Department of Biomedical Engineering, State University of New York at Stony Brook , Stony Brook, New York
          Author notes
          Address for reprint requests and other correspondence: D. Zhu, Dept. of Biomedical Engineering, Univ. of North Texas, Denton, TX 76207 (e-mail: Donghui.Zhu@ 123456unt.edu ).
          PMC5966790 PMC5966790 5966790 C-00279-2017 C-00279-2017
          Copyright © 2018 the American Physiological Society
          Funded by: HHS | NIH | National Institute of General Medical Sciences (NIGMS) 10.13039/100000057
          Award ID: 1R01HL140562
          Research Article

          vascular tone regulation,inflammation,gene regulation,cell signaling,angiogenesis


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