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

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          Abstract

          Zn2+ is an essential element for cell survival/growth, and its deficiency is linked to many disorders. Extracellular Zn2+ 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 Zn2+-sensing receptor ZnR/G protein-coupled receptor 39 (GPR39), found in tissues where dynamic Zn2+ homeostasis takes place, enables extracellular Zn2+ to trigger intracellular signaling pathways regulating key cell functions in vascular cells. Thus, we investigated how extracellular Zn2+ regulates cell viability, proliferation, motility, angiogenesis, vascular tone, and inflammation through ZnR/GPR39 in endothelial cells. Knockdown of GPR39 through siRNA largely abolished Zn2+-triggered cellular activity changes, Ca2+ responses, as well as the downstream activation of Gαq-PLC pathways. Extracellular Zn2+ 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 Zn2+ were not observed in GPR39-/- endothelial cells. Zn2+ 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 Zn2+ regulates endothelial cell activity in a ZnR/GPR39-dependent manner and through the downstream Gαq-PLC pathways. Thus, ZnR/GPR39 may be a therapeutic target for regulating endothelial activity.

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          Author and article information

          Journal
          Am. J. Physiol., Cell Physiol.
          American journal of physiology. Cell physiology
          American Physiological Society
          1522-1563
          0363-6143
          April 01 2018
          : 314
          : 4
          Affiliations
          [1 ] Department of Biomedical Engineering, University of North Texas , Denton, Texas.
          [2 ] Department of Materials Science and Engineering, College of Engineering, Peking University , Beijing , China.
          [3 ] Department of Biomedical Engineering, The City College of the City University of New York , New York, New York.
          [4 ] Department of Bioengineering, University of Texas at Arlington , Arlington, Texas.
          [5 ] Department of Biomedical Engineering, State University of New York at Stony Brook , Stony Brook, New York.
          Article
          10.1152/ajpcell.00279.2017
          5966790
          29351417
          f6bc8a96-f4b2-4814-a33d-f82c655c7af0
          History

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

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