锌转运体Zip2在心肌缺血再灌注损伤中的作用

Impairment of zinc homeostasis characterized by a loss of zinc during reperfusion is associated with myocardial reperfusion injury。Understanding of the intrinsic mechanism by which cardiac cells maintain zinc homeostasis is, therefore, important for the prevention of myocardial reperfusion injury.Our recent studies have demonstrated that the maintenance of zinc homeostasis through zinc supplementation or prevention of zinc loss at reperfusion could protect the heart from reperfusion injury. However，little is known about how the zinc dyshomeostasis at reperfusion is modified. The zinc transporter Zip2 is the most important zinc transporter in the setting of zinc deficiency and plays a critical role in the maintenance of zinc homeostasis. The overall objective of this project is to investigate the exact role of the zinc transporter Zip2 in myocardial reperfusion injury and to explore the mechanism by which Zip2 expression is regulated during reperfusion.This project will adopt the methods of physiology, pharmacology, molecular biology, and genetics to test the hypothesis that the loss of zinc upon reperfusion results in Zip2 upregulation through STAT3 and Zip2 protects the heart from reperfusion injury by correcting zinc dyshomeostasis. This project will not only provide new insights into the role of the zinc transporter in myocardial reperfusion injury but also help us to find new targets and strategies for the prevention of myocardial reperfusion injury.

以锌丢失为特征的心肌锌稳态的失衡与心肌再灌注损伤密切相关，因此阐明心肌内源性锌稳态维持机制对于心肌再灌注损伤的防治具有重要意义。本课题组近几年的研究表明，再灌注期补锌或防止锌离子丢失以维持锌稳态可保护再灌注心脏，但再灌注时锌稳态失衡的内源性纠正机制尚不清楚，是亟待解决的问题。Zip2是细胞缺锌状态下最重要的锌转运体，为细胞锌稳态的维持起着至关重要的作用。本项目的研究目的是探讨Zip2在心肌再灌注损伤中的作用并揭示再灌注时Zip2表达的调控机制。为此，本项目将利用生理学、药理学、分子生物学及基因调控技术等多种方法验证以下假设：再灌注时心肌锌离子的丢失通过信号转导与转录因子3（STAT3）诱导Zip2锌转运体的表达上调，Zip2通过纠正锌稳态的失衡而保护再灌注心脏。本项目的研究不仅揭示锌转运体在再灌注损伤中的作用，还将有助于发现治疗再灌注损伤的新的靶点和方法。

以锌丢失为特征的心肌锌稳态的失衡与心肌再灌注损伤密切相关，因此阐明心肌内源性锌稳态维持机制对于心肌再灌注损伤的防治具有重要意义。Zip2是细胞缺锌状态下最重要的锌转运体，为细胞锌稳态的维持起着至关重要的作用。本项目的研究目的是探讨Zip2在心肌再灌注损伤中的作用并揭示再灌注时Zip2表达的调控机制。本课题的主要研究内容包括：1）探讨再灌注期心肌Zip2的表达是否增加；2）明确Zip2在再灌注损伤中的作用；3）揭示再灌注期Zip2表达增加的调控机制。本课题证实了再灌注时心肌锌离子的丢失通过STAT3诱导锌转运体Zip2的表达，Zip2通过纠正锌稳态的失衡而保护再灌注心脏。本研究最重要的发现为：我们利用生理学，分子生物学等手段首次明确了再灌注时心肌锌离子的丢失通过诱导内质网应急而激活STAT3，激活了的STAT3引起Zip2 的上调，敲除Zip2基因明显恶化小鼠心肌缺血再灌注损伤，提示Zip2可能通过纠正锌稳态的失衡而保护再灌注心脏。本研究的发现不仅有助于了解心肌细胞内源性再灌注损伤保护机制，而且为再灌注损伤的治疗提供新靶点。