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首页> 外文期刊>Circulation journal >Thromboxane A2 Mediates Iron-Overload Cardiomyopathy in Mice Through Calcineurin-Nuclear Factor of Activated T Cells Signaling Pathway
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Thromboxane A2 Mediates Iron-Overload Cardiomyopathy in Mice Through Calcineurin-Nuclear Factor of Activated T Cells Signaling Pathway

机译：血栓烷A 2 通过钙调神经磷酸酶-核因子激活的T细胞信号转导通路介导小鼠铁超负荷心肌病。

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Background: ?Recent studies demonstrated that iron overload could enhance the production of arachidonic acid and prostanoid, suggesting a causal connection between these signals and iron-overload cardiomyopathy. However, information regarding the downstream signaling is limited. Because thromboxane A2 (TXA2) and prostacyclin are the 2 major prostanoids in the cardiovascular system, and TXA2 plays a major role in vascular atherosclerosis and has pro-inflammatory characteristics, we intended to elucidate the role of TXA2 in iron-overload cardiomyopathy. Methods and Results: ?A 4-week iron loading protocol was instituted for both TXAS gene-deleted (TXAS?/?) mice and wild-type (WT) mice, with less severe cardiac fibrosis and preserved normal left ventricular contraction in the TXAS?/? mice. Inflammatory profiles, including MCP-1, TNF-α, IL-6, ICAM-1, and myeloperoxidase activity were also lower in the TXAS?/? as compared with WT littermates. TXAS supplement to the iron-injured TXAS?/? mice re-aggravated cardiac inflammation. Using a TXA2 analog, U46619, for NFAT reporter luciferase activity on cardiomyoctes, and intraperitonal injection of U46619 into nuclear factor of activated T cells (NFAT)-luciferase transgenic mice demonstrated that U46619 increase NFAT expression, and this expression, as well as TNF-α expression, can be blocked by TXA2 receptor antagonist (SQ29548), NFAT-SiRNA, calcineurin inhibitor, or calcium chelator. Finally, intraperitoneal injection of the TNF-α antibody, infliximab, into iron-injured mice decreased TXAS expression and attenuated cardiac fibrosis. Conclusions: ?TXA2 mediates iron-overload cardiomyopathy through the TNF-α-associated calcineurin-NFAT signaling pathway.??( Circ J ?2013; 77: 2586–2595)
机译：背景：？最近的研究表明，铁超负荷可增强花生四烯酸和前列腺素的产生，表明这些信号与铁超负荷心肌病之间存在因果关系。然而，关于下游信令的信息是有限的。因为血栓烷A 2 （TXA 2 ）和前列环素是心血管系统中的两种主要类前列腺素，而TXA 2 在血管中起主要作用动脉粥样硬化并具有促炎特性，我们旨在阐明TXA 2 在铁超负荷心肌病中的作用。方法和结果：针对缺失TXAS基因的（TXAS ？/？）小鼠和野生型（WT）小鼠建立了4周的铁负荷方案，心脏纤维化程度较轻且保留TXAS ？/？小鼠的正常左心室收缩。与WT同窝仔猪相比，TXAS α/β中的炎症特征，包括MCP-1，TNF-α，IL-6，ICAM-1和髓过氧化物酶活性也较低。铁损伤的TXAS ？/？小鼠的TXAS补充剂使心脏炎症加重。使用TXA 2 类似物U46619增强心肌NFAT荧光素酶的活性，并向活化T细胞核因子（NFAT）-荧光素酶转基因小鼠腹膜内注射U46619，证明U46619增加NFAT的表达，并且TXA 2 受体拮抗剂（SQ29548），NFAT-SiRNA，钙调神经磷酸酶抑制剂或钙螯合剂可阻断这种表达以及TNF-α表达。最后，向铁损伤的小鼠腹膜内注射TNF-α抗体英夫利昔单抗可降低TXAS表达并减轻心脏纤维化。结论：？TXA 2 通过TNF-α相关的钙调神经磷酸酶-NFAT信号通路介导铁超负荷心肌病。（Circ J？2013; 77：2586-2595）

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