Department of Physiology & Pathophysiology, Tianjin Medical University, Tianjin 300070, China; Department of Anesthesiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Anesthesia and Pain Medicine, Chonnam National University, Guangju, South Korea.
J Mol Cell Cardiol. 2014 Jan;66:12-7. doi: 10.1016/j.yjmcc.2013.10.016. Epub 2013 Oct 31.
This study investigated if zinc plays a role in postconditioning-induced cardioprotection in rat hearts. Isolated rat hearts were subjected to 30 min regional ischemia followed by 2h of reperfusion. Postconditioning was elicited by 6 cycles of 10s reperfusion and 10s ischemia. Cytosolic zinc concentrations were measured with inductively coupled plasma optical emission spectroscopy (ICPOES). Infarct size was assessed by triphenyltetrazolium chloride staining. Cytosolic zinc concentrations were decreased dramatically upon reperfusion in the control hearts. In contrast, postconditioning increased cytosolic zinc levels at reperfusion. The anti-infarct effect of postconditioning was inhibited by the selective zinc chelator N,N,N',N'-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN). Postconditioning significantly increased phosphorylation levels of the reperfusion injury salvage kinases (RISK) including Akt (Ser(473)), extracellular signal-regulated kinase1/2 (ERK1/2) (Thr(202)/Tyr(204)), and glycogen synthase kinase-3β (GSK-3β) (Ser(9)) at reperfusion, which were nullified by TPEN. Postconditioning decreased the activity of protein phosphatase 2A (PP2A) in a zinc-dependent manner. Knockdown of the zinc transporter Zip2 inhibited the protective effect of postconditioning on hypoxia/reoxygenation injury in H9c2 cells. These results suggest that zinc plays an important role in the cardioprotective effect of postconditioning presumably by enhancing the activation of the RISK pathway. Zip2 and inactivation of PP2A by zinc may, at least in part, account for the activation of the RISK pathway.
本研究旨在探讨锌是否在大鼠心脏后处理诱导的心肌保护中发挥作用。分离的大鼠心脏经历 30 分钟的局部缺血,随后进行 2 小时的再灌注。后处理通过 6 个循环的 10 秒再灌注和 10 秒缺血来诱发。通过电感耦合等离子体发射光谱(ICPOES)测量细胞质锌浓度。通过氯化三苯基四氮唑染色评估梗死面积。在对照心脏中,再灌注时细胞质锌浓度急剧下降。相比之下,后处理增加了再灌注时细胞质锌水平。选择性锌螯合剂 N,N,N',N'-四(2-吡啶甲基)乙二胺(TPEN)抑制了后处理的抗梗死作用。后处理显著增加了再灌注损伤挽救激酶(RISK)的磷酸化水平,包括 Akt(Ser(473))、细胞外信号调节激酶 1/2(ERK1/2)(Thr(202)/Tyr(204))和糖原合成酶激酶-3β(GSK-3β)(Ser(9)),而这些在再灌注时被 TPEN 消除。后处理以锌依赖的方式降低蛋白磷酸酶 2A(PP2A)的活性。锌转运体 Zip2 的敲低抑制了后处理对 H9c2 细胞缺氧/复氧损伤的保护作用。这些结果表明,锌在后处理的保护作用中发挥重要作用,可能通过增强 RISK 途径的激活。Zip2 和锌对 PP2A 的失活至少部分解释了 RISK 途径的激活。