锌转运体Zip2对心肌缺血再灌注小鼠心肌线粒体呼吸的调控作用
王丽艳, 程欣欣, 徐哲龙^*
天津医科大学基础医学院生理学与病理生理学系，天津 300070
摘要
本研究旨在探讨锌转运体Zip2 (SLC39A2)在心肌缺血再灌注(ischemia/reperfusion, I/R)过程中对线粒体呼吸的调控作用及其机制。通过冠状动脉左前降支结扎建立小鼠在体心肌I/R损伤模型，用电感耦合离子发射光谱仪(inductively coupledplasma-optical emission spectrometer, ICP-OES)测量心肌组织的锌含量，用高分辨呼吸测定系统(Oxygraph-2K)检测小鼠心肌线粒体呼吸功能和氧化磷酸化水平，采用Western blot技术检测小鼠心肌组织STAT3和ERK的磷酸化水平。结果显示：(1)与假手术组相比，野生型小鼠I/R心肌组织的锌含量明显降低，Zip2基因敲除小鼠I/R心肌组织的锌含量进一步降低；(2) 与野生对照组相比，Zip2基因敲除组小鼠心肌线粒体呼吸控制率(respiratory control ratio, RCR)和氧化磷酸化水平降低，I/R后上述指标进一步降低；(3)与野生对照组相比，I/R后Zip2基因敲除组小鼠心肌组织STAT3 (Ser727)和ERK的蛋白磷酸化水平均明显降低；(4)与空载体感染组相比，I/R后STAT3感染组心肌线粒体呼吸功能明显提高，而STAT3负突变体感染组心肌线粒体呼吸功能则降低。STAT3过表达可逆转Zip2基因敲除对线粒体呼吸的抑制作用。以上结果提示，心肌I/R时Zip2通过STAT3来调控线粒体呼吸，其机制可能与STAT3 (Ser727)的磷酸化有关，这可能是Zip2保护心肌的分子机制之一。
关键词： 锌; 锌转运蛋白Zip2; 缺血再灌注损伤; STAT3; 线粒体呼吸
分类号：R363

Regulatory effect of the zinc transporter Zip2 on cardiomyocyte mitochondrial respiration function after cardiac ischemia-reperfusion injury in mice
WANG Li-Yan, CHENG Xin-Xin, XU Zhe-Long^*
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Abstract
The aim of the present study was to investigate the effect of zinc transporter Zip2 (SLC39A2) on mitochondrial respiration during myocardial ischemia/reperfusion (I/R) and the underlying mechanisms. An in vivo myocardial I/R model was established in mice by ligation of left anterior descending coronary artery. Cardiac zinc concentration was measured by inductively coupled plasma- optical emission spectrometer (ICP-OES), and the mitochondrial respiratory function and oxidative phosphorylation were determined by high-resolution respirometry (Oxygraph-2K). The phosphorylation levels of STAT3 and ERK in myocardial tissue were detected by Western blot. The results showed that, compared with the sham group, cardiac zinc concentration in myocardium was decreased in wild-type mice and further reduced in Zip2 knockout mice after I/R. Mitochondrial respiratory control rate (RCR) and oxidative phosphorylation were decreased in Zip2 knockout mice and worsened by I/R. Phosphorylation levels of STAT3 (Ser727) and ERK were significantly decreased in Zip2 knockout mice after I/R. In I/R myocardial tissue, STAT3 overexpression significantly improved the mitochondrial respiratory function, while STAT3 dominant negative mutant (STAT3 S727A) inhibited mitochondrial respiratory function. Moreover, the impairment of mitochondrial function by Zip2 knockout was reversed by STAT3 overexpression. These results suggest that Zip2 regulates mitochondrial respiration via phosphorylation of STAT3 during myocardial I/R, which may represent the underlying mechanism of Zip2 cardioprotection against I/R injury.
Key words: Zinc; zinc transporter Zip2; ischemia/reperfusion injury; STAT3; mitochondrial respiration

收稿日期：2019-11-19　　录用日期：2020-03-20
通讯作者：徐哲龙　　E-mail: zxu@tmu.edu.cn
DOI: 10.13294/j.aps.2020.0041
引用本文：
王丽艳, 程欣欣, 徐哲龙. 锌转运体Zip2对心肌缺血再灌注小鼠心肌线粒体呼吸的调控作用[J]. 生理学报 2020; 72 (4): 433-440.
WANG Li-Yan, CHENG Xin-Xin, XU Zhe-Long. Regulatory effect of the zinc transporter Zip2 on cardiomyocyte mitochondrial respiration function after cardiac ischemia-reperfusion injury in mice. Acta Physiol Sin 2020; 72 (4): 433-440 (in Chinese with English abstract).



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