Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China.
Department of Cardiology, General Hospital, Tianjin Medical University, Tianjin 300052, China.
J Mol Cell Cardiol. 2019 Jul;132:136-145. doi: 10.1016/j.yjmcc.2019.05.011. Epub 2019 May 13.
Although zinc homeostasis has been demonstrated to play a role in myocardial ischemia/reperfusion (I/R) injury, the roles of zinc transporters that are critical for zinc homeostasis in I/R injury are poorly understood. The purpose of this study was to test if Zip2, an important zinc importer, plays a role in I/R injury in mouse hearts and explore the mechanism by which Zip2 expression is regulated. Zip2 expression was increased at reperfusion in in vivo mouse hearts, an effect that was abolished by ZnCl, indicating Zip2's attempt to compensate for zinc loss at reperfusion. Further studies showed that upregulation of Zip2 expression was reversed by either pharmacological or genetic inhibition of signal transducers and activators of transcription 3 (STAT3), whereas STAT3 overexpression increased Zip2 expression, indicating that STAT3 accounts for Zip2 upregulation. In support, reperfusion enhanced STAT3 phosphorylation (Tyr), which was blocked by ZnCl, implying that STAT3 is activated in response to zinc loss. To determine the role of Zip2 in I/R injury, we assessed I/R injury by genetically disrupting Zip2 expression. Knockout of Zip2 genes (Zip2 and Zip2) exacerbated I/R injury by increasing infarct size as well as the serum LDH, troponin I (cTnI), and CK-MB activities. In contrast, delivery of Zip2 genes reduced I/R injury. Delivery of STAT3 genes increased STAT3 phosphorylation and reduced I/R injury. However, delivery of the dominant negative STAT3 mutant did not reduce I/R injury. Moreover, delivery of STAT3 genes failed to reduce I/R injury in Zip2 mice. Zip2 upregulated upon reperfusion via STAT3 is cardioprotective and this upregulation may serve as an important intrinsic protective mechanism by which the heart is resistant to I/R injury. The factors involved in the zinc homeostasis (zinc and Zip2) are responsible STAT3 activation and its subsequent cardioprotective action.
尽管锌稳态已被证明在心肌缺血/再灌注（I/R）损伤中发挥作用，但对于锌稳态中关键的锌转运体在 I/R 损伤中的作用知之甚少。本研究旨在测试重要锌内流体 Zip2 在小鼠心脏 I/R 损伤中是否发挥作用，并探讨 Zip2 表达受调控的机制。在体内小鼠心脏中，再灌注时 Zip2 表达增加，而 ZnCl 可消除这种作用，表明 Zip2 试图在再灌注时补偿锌的丢失。进一步的研究表明，通过药理学或遗传学抑制信号转导和转录激活因子 3（STAT3）可逆转 Zip2 表达的上调，而 STAT3 过表达可增加 Zip2 的表达，表明 STAT3 可导致 Zip2 的上调。支持这一观点的是，再灌注增强了 STAT3 的磷酸化（Tyr），而 ZnCl 可阻断这一作用，表明 STAT3 是对锌丢失的反应而被激活的。为了确定 Zip2 在 I/R 损伤中的作用，我们通过基因敲除的方法破坏 Zip2 的表达。Zip2 基因（Zip2 和 Zip2）敲除加剧了 I/R 损伤，增加了梗死面积以及血清 LDH、肌钙蛋白 I（cTnI）和 CK-MB 活性。相反，Zip2 基因的表达则减轻了 I/R 损伤。STAT3 基因的表达增加了 STAT3 的磷酸化并减轻了 I/R 损伤。然而，表达显性失活的 STAT3 突变体并不能减轻 I/R 损伤。此外，STAT3 基因的表达在 Zip2 小鼠中未能减轻 I/R 损伤。再灌注时 Zip2 通过 STAT3 上调具有心脏保护作用，这种上调可能是心脏抵抗 I/R 损伤的重要内在保护机制。锌稳态（锌和 Zip2）相关的因素负责 STAT3 的激活及其随后的心脏保护作用。
