title: ClC-3 deficiency prevents atherosclerotic lesion development in ApoE-/- mice.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China; Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Tao
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Can-Zhao
authors.initials: CZ
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Zhi-Zhong
authors.initials: ZZ
authors.lastname: Xie
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Xiang-Yu
authors.initials: XY
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Fei-Ya
authors.initials: FY
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Guan-Lei
authors.initials: GL
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Jia-Guo
authors.initials: JG
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China. Electronic address: duyanhua@mail.sysu.edu.cn.
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Du
authors.affiliation: Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China. Electronic address: guanyy@mail.sysu.edu.cn.
authors.forename: Yong-Yuan
authors.initials: YY
authors.lastname: Guan
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018118:Chloride Channels / Q000172:deficiency / Q000235:genetics*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D051117:Scavenger Receptors, Class A / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D018118:Chloride Channels; C115376:ClC-3 channel; D051117:Scavenger Receptors, Class A
keywords: Atherosclerosis; ClC-3; Foam cell; MAPK; Scavenger receptor