The critical role of intracellular zinc in adenosine A(2) receptor activation induced cardioprotection against reperfusion injury.
The critical role of intracellular zinc in adenosine A(2) receptor activation induced cardioprotection against reperfusion injury.
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DOI：
10.1016/j.yjmcc.2010.02.001
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发表时间：
2010-07
影响因子：
5
通讯作者：
Xu Z
中科院分区：
文献类型：
--
作者：
McIntosh R;Lee S;Ghio AJ;Xi J;Zhu M;Shen X;Chanoit G;Zvara DA;Xu Z
外源性锌可以保护心肌细胞免受再灌注损伤，但内源性锌在再灌注损伤的发病机制和腺苷A2受体激活诱导的心脏再灌注损伤保护中的确切作用尚不清楚。再灌注时给予腺苷A1/A2受体激动剂5 ' -（n -乙基羧胺）腺苷（NECA）可减少离体大鼠心脏缺血30分钟后再灌注2小时的梗死面积。锌螯合剂N，N,N ',N ' -四akis-（2-吡啶基甲基）乙二胺（TPEN）部分但显著阻断了NECA的这种作用，再灌注时给予ZnCl2通过减少梗死面积来模拟NECA的作用。用电感耦合等离子体光学发射光谱（ICPOES）测定大鼠心脏再灌注后总组织锌浓度降低，NECA可逆转这一趋势。在心脏再灌注期间，NECA增加了细胞内游离锌。共聚焦成像研究显示，经NECA处理的离体大鼠心肌细胞胞内游离锌迅速增加。进一步的实验表明，NECA增加了离体心脏分离的线粒体再灌注时的总锌水平。NECA可减轻离体心脏再灌注时的线粒体肿胀，而TPEN可抑制这种肿胀。同样，NECA防止心肌细胞氧化应激引起的线粒体膜电位丧失（ΔΨm）。最后，NECA和ZnCl2均抑制线粒体代谢活性。neca诱导的心脏再灌注损伤保护是由细胞内锌介导的。NECA防止再灌注引起的锌损失，并将锌重新定位到线粒体。锌对mPTP开放和线粒体代谢活性的抑制作用可能解释了NECA的心脏保护作用。
Exogenous zinc can protect cardiac cells from reperfusion injury, but the exact roles of endogenous zinc in the pathogenesis of reperfusion injury and in adenosine A2 receptor activation-induced cardioprotection against reperfusion injury remain unknown. Adenosine A1/A2 receptor agonist 5′-(N-ethylcarboxamido) adenosine (NECA) given at reperfusion reduced infarct size in isolated rat hearts subjected to 30 min ischemia followed by 2 h of reperfusion. This effect of NECA was partially but significantly blocked by the zinc chelator N,N,N′,N′-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN), and ZnCl2 given at reperfusion mimicked the effect of NECA by reducing infarct size. Total tissue zinc concentrations measured with inductively coupled plasma optical emission spectroscopy (ICPOES) were decreased upon reperfusion in rat hearts and this was reversed by NECA. NECA increased intracellular free zinc during reperfusion in the heart. Confocal imaging study showed a rapid increase in intracellular free zinc in isolated rat cardiomyocytes treated with NECA. Further experiments revealed that NECA increased total zinc levels upon reperfusion in mitochondria isolated from isolated hearts. NECA attenuated mitochondrial swelling upon reperfusion in isolated hearts and this was inhibited by TPEN. Similarly, NECA prevented the loss of mitochondrial membrane potential (ΔΨm) caused by oxidant stress in cardiomyocytes. Finally, both NECA and ZnCl2 inhibited the mitochondrial metabolic activity. NECA-induced cardioprotection against reperfusion injury is mediated by intracellular zinc. NECA prevents reperfusion-induced zinc loss and relocates zinc to mitochondria. The inhibitory effects of zinc on both the mPTP opening and the mitochondrial metabolic activity may account for the cardioprotective effect of NECA.
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DOI：
10.1152/ajpheart.495.2008
发表时间：
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影响因子：
4.8
作者：
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影响因子：
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作者：
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影响因子：
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