ClC-3 deficiency prevents atherosclerotic lesion development in ApoE-/- mice
ClC-3 deficiency prevents atherosclerotic lesion development in ApoE-/- mice
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DOI：
10.1016/j.yjmcc.2015.09.002
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发表时间：
2015-10-01
影响因子：
5
通讯作者：
Guan, Yong-Yuan
中科院分区：
文献类型：
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作者：
Tao, Jing;Liu, Can-Zhao;Guan, Yong-Yuan
背景资料：最近的证据表明，ClC-3，编码Cl通道或Cl-/H+反向转运蛋白，在调节多种生理功能中起着关键作用。然而，对于ClC-3是否参与动脉粥样硬化知之甚少。本研究旨在通过使用ClC-3和ApoE双缺陷小鼠建立ClC-3在动脉粥样硬化形成中的参与和直接作用及其潜在机制。方法和结果：在16周的西式高脂饮食后，ClC-3（+/+）ApoE（-/-）小鼠在主动脉中发展出广泛的动脉粥样硬化病变。而ClC-3（-/-）ApoE（-/-）小鼠的主动脉病变尺寸显著减小。与ClC-3（+/+）对照组相比，ClC-3（-/-）小鼠腹腔巨噬细胞对ox-LDL的结合和摄取明显降低。此外，清道夫受体SR-A的表达，而不是CD 36，在ClC-3（-/-）ApoE（-/-）小鼠的ClC-3（-/-）腹腔巨噬细胞和主动脉病变中显著降低。这些发现在ox-LDL处理的RAW264.7巨噬细胞中得到进一步证实，这表明ClC-3的沉默抑制SR-A表达、ox-LDL积累和泡沫细胞形成，而ClC-3的过表达产生相反的效果。此外，ClC-3 siRNA显著抑制ox-LDL处理的RAW264.7泡沫细胞中JNK/p38 MAPK的磷酸化，而ClC-3过表达增加。JNK或p38抑制剂预处理可阻断ClC-3诱导的SR-A表达和ox-LDL摄取的增加。最后，增加JNK/p38磷酸化和SR-A的表达，由ClC-3诱导可以模仿减少[Cl-]（i）由低Cl- solution.Conclusions：我们的研究结果表明，ClC-3缺乏抑制动脉粥样硬化病变的发展，可能通过抑制JNK/p38 MAPK依赖的SR-A的表达和泡沫细胞的形成。(C)2015爱思唯尔有限公司版权所有。
Background: Recent evidence suggested that ClC-3, encoding Cl channel or Cl-/H+ antiporter, plays a critical role in regulation of a variety of physiological functions. However, remarkably little is known about whether ClC-3 is involved in atherosclerosis. This study aims to establish the involvement and direct role of ClC-3 in atherogenesis and underlying mechanisms by using ClC-3 and ApoE double null mice.Methods and results: After a 16-week western-type high-fat diet, the ClC-3(+/+)ApoE(-/-) mice developed widespread atherosclerotic lesions in aorta. However, the lesion size was significantly reduced in aorta of ClC-3(-/-) ApoE(-/-) mice. Compared with the ClC-3(+/+) controls, there was significantly decreased ox-LDL binding and uptake in isolated peritoneal macrophages from ClC-3(-/-) mice. Moreover, the expression of scavenger receptor SR-A, but not CD36, was significantly decreased in both ClC-3(-/-) peritoneal macrophages and aortic lesions from ClC-3(-/-)ApoE(-/-) mice. These findings were further confirmed in ox-LDL-treated RAW264.7 macrophages, which showed that silence of ClC-3 inhibited SR-A expression, ox-LDL accumulation and foam cell formation, whereas overexpression of ClC-3 produced the opposite effects. In addition, ClC-3 siRNA significantly inhibited, whereas ClC-3 overexpression increased, the phosphorylation of JNK/p38 MAPK in ox-LDL-treated RAW264.7 foam cells. Pretreatment with JNK or p38 inhibitor abolished ClC-3-induced increase in SR-A expression and ox-LDL uptake. Finally, the increased JNK/p38 phosphorylation and SR-A expression induced by ClC-3 could be mimicked by reduction of [Cl-](i) by low Cl- solution.Conclusions: Our findings demonstrated that ClC-3 deficiency inhibits atherosclerotic lesion development, possibly via suppression of JNK/p38 MAPK dependent SR-A expression and foam cell formation. (C) 2015 Elsevier Ltd. All rights reserved.