SLC41A1 knockdown inhibits angiotensin II-induced cardiac fibrosis by preventing Mg(2+) efflux and Ca(2+) signaling in cardiac fibroblasts.
SLC41A1 knockdown inhibits angiotensin II-induced cardiac fibrosis by preventing Mg(2+) efflux and Ca(2+) signaling in cardiac fibroblasts.
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DOI：
10.1016/j.abb.2014.09.013
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发表时间：
2014-12
影响因子：
3.9
通讯作者：
Na Yu;Jianmin Jiang;Yang Yu;Hong Li;Xiao-yang Huang;Yunzi Ma;Luankun Zhang;J. Zou;Boyu Zhang;Shaorui Chen;Peiqing Liu
中科院分区：
文献类型：
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作者：
Na Yu;Jianmin Jiang;Yang Yu;Hong Li;Xiao-yang Huang;Yunzi Ma;Luankun Zhang;J. Zou;Boyu Zhang;Shaorui Chen;Peiqing Liu
Na+/Mg~(2+)交换体在心血管系统中起着重要作用，但其分子机制仍不清楚。溶质载体家族41a1(Slc41a1)是近年来发现的一种新型的镁离子转运体，具有钠/镁离子交换功能，主要调节细胞内镁离子([Mg2+]i)的动态平衡。我们目前的研究旨在探讨SLC41a1在血管紧张素II刺激下是否影响心脏成纤维细胞的纤维化形成。结果表明，Na+/Mg~(2+)交换的典型抑制剂奎尼丁可抑制血管紧张素转换酶II诱导的心肌纤维化，其机制可能是通过抑制结缔组织生长因子、纤维连接蛋白和α-平滑肌肌动蛋白(α-SMA)等重要纤维化标志物的过度表达。此外，奎尼丁还可降低Ang II引起的细胞内钙离子浓度升高和细胞内镁离子排出。同时，RNA干扰沉默SLC41a1siRNA细胞内[Ca~(2+)]i、[Mg~(2+)]i外流以及血管紧张素Ⅱ诱导的CTGF、FN和α-SMA的上调也受到抑制。这些结果支持细胞内镁离子的快速排出是由SLC41a1介导的，并提供了细胞内游离钙离子浓度受促进心肌成纤维细胞纤维化反应的镁离子排出的影响的证据。
Na+/Mg2+exchanger plays an important role in cardiovascular system, but the molecular mechanisms still largely remain unknown. The Solute Carrier family 41A1 (SLC41A1), a novel Mg2+transporter, recently was found to function as Na+/Mg2+exchanger, which mainly regulates the intracellular Mg2+([Mg2+]i) homeostasis. Our present studies were designed to investigate whether SLC41A1 impacts on the fibrogenesis of cardiac fibroblasts under Ang II stimulation. Our results showed that quinidine, a prototypical inhibitor of Na+/Mg2+exchanger, inhibited Ang II-induced cardiac fibrosis via attenuating the overexpression of vital biomarkers of fibrosis, including connective tissue growth factor (CTGF), fibronectin (FN) and α-smooth muscle actin (α-SMA). In addition, quinidine also decreased the Ang II-mediated elevation of concentration of intracellular Ca2+([Ca2+]i) and extrusion of intracellular Mg2+. Meanwhile, silencing SLC41A1 by RNA interference also impaired the elevation of [Ca2+]i, [Mg2+]iefflux and the upregulation of CTGF, FN and α-SMA provoked by Ang II. Furthermore, we found that Ang II-mediated activation of NFATc4 translocation decreased in SLC41A1-siRNA cells. These results support the notion that rapid extrusion of intracellular Mg2+is mediated by SLC41A1 and provide the evidence that the intracellular free Ca2+concentration is influenced by extrusion of intracellular Mg2+which facilitates fibrosis reaction in cardiac fibroblasts.