Upregulation of Zip14 correlates with induction of endoplasmic reticulum stress(ERS)in hypertrophied hearts of Dahl saltsensitive rats

Zinc is a trace element involved in maintaining cellular structure and function.Although zinc is associated with left ventricular hypertrophy(LVH),there have been few reports on this association.This study aimed to evaluate the correlation between Zip14 and expression of endoplasmic reticulum stress(ERS)associated molecules in hypertrophied hearts of rats.Dahl salt-sensitive rats were fed a high salt diet to establish a left ventricular hypertrophy(LVH)rat model.RT-PCR was used to determine Zip14,activating transcription factor(ATF4),ATF6,x-box-binding protein 1(xBP1),C/EBP homologous protein(CHOP),immunoglobulin-binding protein(BiP)mRNA expression.Western blotting was used to evaluate Zip14,BiP,CHOP,GAPDH expression.Zinc levels were measured by Inductively Coupled Plasma Optical Emission Spectroscopy.The results indicated that compared with the Control group,Zip14 mRNA and protein expression in LVH rat hearts were markedly increased(P<0.01).Zinc content in rat heart tissue was significantly increased in the LVH group compared with the Control group(P<0.05).ATF4,ATF6,xBP1 mRNA expressions were increased in LVH rat hearts compared with Control hearts(P<0.001).Compared with the Control group,CHOP and BiP mRNA and protein expression were markedly increased in LVH rat hearts(P<0.05,P<0.01).Linear regression models showed that Zip14 mRNA expressions were positively correlated with zinc concentration,ATF4 and ATF6 mRNA expressions in Control hearts(P=0.0005,P=0.0052,P=0.0026,respectively)and LVH rat hearts(P<0.0001,P=0.0119,P=0.0033,respectively).In conclusion,upregulation of Zip14 in LVH rat hearts correlated with zinc accumulation and induction of ERS.

ZIP14的表达及功能分析

目的基于TCGA数据库研究胶质瘤锌转运蛋白家族分子的表达变化,探究对胶质瘤患者有预后意义的转运蛋白分子,并整合生物信息学研究其促胶质瘤进展的机制。方法通过研究胶质母细胞瘤与非肿瘤脑组织锌转运蛋白的表达差异,分析转运蛋白分子与总生存率、肿瘤级别的关联,通过生物信息学软件对分子进行功能学注释。结果与非肿瘤脑组织相比,ZIP1,6,7,8,14和ZnT4,5在胶质母细胞瘤中上调,ZnT3,10在胶质母细胞瘤中下调。ZIP14表达随胶质瘤级别增高而上调,且是胶质瘤患者预后的独立预测标志物。GO、GSEA、GSVA结果显示ZIP14与细胞迁移、凋亡、免疫相关。结论胶质瘤中锌转运蛋白家族分子失调,ZIP14或可作为胶质瘤的预后标志物。

射血分数保留的心力衰竭大鼠心脏锌积累和内质网应激的诱导

目的在建立射血分数保留心力衰竭(HFpEF)大鼠模型的基础上,检测HFpEF大鼠心肌锌离子浓度及锌转运体Zip14表达的改变以及证实HFpEF大鼠心肌内质网应激和炎症的存在。方法采用达尔盐敏感大鼠(DSS)高盐饮食建立HFpEF动物模型,DSS大鼠随机分为高盐饮食组(HS组)和正常饮食组(NS组)。各组动物均每两周测量一次无创血压和心率,分别在第6周、12周、19周检测两组大鼠的心脏超声指标。麻醉并处死符合HFpEF模型标准以及同时期对照组的大鼠,快速分离左心室心肌并-80℃冰箱保存。应用电感耦合等离子原子发射光谱法(ICP-OES)测定心肌组织的锌离子浓度。RT-fq-PCR和WB分别检测心肌组织锌转运体Zip14的mRNA和蛋白表达水平。研究进一步使用RT-fq-PCR法检测心肌组织内质网应激相关因子ATF6、ATF4、CHOP、Bip和xBPI的mRNA表达水平。WB法检测内质网应激相关因子CHOP、Bip和炎症相关转录因子NF-κB p65的蛋白表达水平。结果在第19周时,与正常饮食组相比,高盐饮食组DSS大鼠的SBP、LVM和LVM/W明显升高,而两组EF比较,差异无统计学意义。HFpEF组大鼠心肌组织的锌离子浓度明显高于对照组。HFpEF组大鼠心肌组织的锌转运体Zip14mRNA和蛋白表达水平明显高于对照组。与对照组相比,HFpEF组大鼠心肌组织的ATF6、ATF4、CHOP、Bip和xBPI的mRNA表达水平明显升高。与对照组相比,HFpEF组大鼠心肌组织的CHOP、Bip和NF-κB p65的蛋白表达水平明显升高。结论 HFpEF大鼠心肌的锌积累与锌转运体Zip14的表达上调、内质网应激以及炎症有一定的相关性,然而,相互之间的具体调节机制有待进一步研究。

金属转运蛋白SLC39A14的生理功能及作用机制研究进展

溶质载体家族39(solute carrier family 39,SLC39;Zrt-and Irt-like proteins,ZIPs)作为金属离子转运蛋白家族共包括14个成员,均具有8个跨膜结构域。近年来,国内外研究者围绕SLC39A14(又称ZIP14)的离子转运及生理功能开展了深入研究,提示SLC39A14具有转运Mn^2+、Fe^2+或Zn^2+等二价金属离子的功能,并通过转运Fe^2+而参与细胞铁死亡的发生。携带SLC39A14基因纯合突变的患者表现为锰离子蓄积及年轻型帕金森样体征。此外,有研究报道SLC39A14在肝脏疾病、胰岛素代谢、脂代谢及肌肉疾病中发挥关键作用,为丰富微量元素代谢调控网络及疾病防控提供了重要理论依据。然而,Slc39a14全身敲除与组织特异性敲除小鼠之间的表型不尽相同,因此其在不同组织中的金属离子转运功能及机制尚待深入研究。该文系统综述了SLC39A14在金属离子转运、代谢紊乱疾病和分子调控机制等方面的研究进展,并就未来研究方向进行了展望和讨论。