The critical role of the zinc transporter Zip2 (SLC39A2) in ischemia/reperfusion injury in mouse hearts.

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 ZnCl₂, 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 whereas overexpression increased Zip2 expression, indicating that duanyu18133 accounts for Zip2 upregulation. In support, reperfusion enhanced duanyu18133 phosphorylation (Tyr⁷⁰⁵), which was blocked by ZnCl₂, implying that duanyu18133 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 duanyu18133 genes increased duanyu18133 phosphorylation and reduced I/R injury. However, delivery of the dominant negative duanyu18133 mutant did not reduce I/R injury. Moreover, delivery of duanyu18133 genes failed to reduce I/R injury in Zip2^-/- mice. Zip2 upregulated upon reperfusion via duanyu18133 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 duanyu18133 activation and its subsequent cardioprotective action.

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