Zinc regulates vascular endothelial cell activity through zinc-sensing receptor ZnR/GPR39.
Zinc regulates vascular endothelial cell activity through zinc-sensing receptor ZnR/GPR39.
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DOI：
10.1152/ajpcell.00279.2017
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发表时间：
2018-04
期刊：
影响因子：
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通讯作者：
Donghui Zhu;Yingchao Su;Yufeng Zheng;B. Fu;Liping Tang;Yi-Xian Qin
中科院分区：
文献类型：
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作者：
Donghui Zhu;Yingchao Su;Yufeng Zheng;B. Fu;Liping Tang;Yi-Xian Qin
Zn 2+是细胞存活/生长的必需元素，其缺乏与许多疾病有关。细胞外Zn 2+浓度变化参与调节基本细胞过程，如增殖、分泌、离子转运和细胞信号转导，其机制尚不清楚。在这里，我们假设，Zn 2+敏感受体ZnR/G蛋白偶联受体39（GPR 39），发现在动态Zn 2+稳态发生的组织，使细胞外Zn 2+触发细胞内信号通路调节血管细胞中的关键细胞功能。因此，我们研究了细胞外Zn 2+如何通过内皮细胞中的ZnR/GPR 39调节细胞活力、增殖、运动性、血管生成、血管张力和炎症。通过siRNA敲低GPR 39在很大程度上消除了Zn 2+触发的细胞活性变化、Ca 2+反应以及Gαq-PLC通路的下游激活。细胞外Zn 2+通过激活cAMP和Akt，以及过表达血小板源性生长因子-α受体和血管内皮生长因子A促进血管细胞存活/生长。它还增强细胞粘附和流动性，内皮小管形成，和细胞骨架重组。在GPR 39-/-内皮细胞中未观察到胞外Zn 2+的这种作用。Zn 2+还调节炎症相关的关键分子，如血红素加氧酶-1、选择素L、IL-10和血小板内皮细胞粘附分子1，以及血管紧张度相关的前列腺素I2合酶和一氧化氮合酶-3。总之，细胞外Zn 2+以ZnR/GPR 39依赖性方式并通过下游Gαq-PLC途径调节内皮细胞活性。因此，ZnR/GPR 39可能是调节内皮活性的治疗靶点。
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.