title: Reduction of Intracellular Chloride Concentration Promotes Foam Cell Formation.
abstract: BACKGROUND
  Previous work has demonstrated that the volume-regulated chloride channel is activated during foam cell formation, and inhibition of chloride movement prevents intracellular lipid accumulation. However, the mechanism explaining how chloride movement promotes foam cell formation is not clear.
  
  
  RESULTS
  Foam cell formation was determined by Oil Red O staining. Western blotting and co-immunoprecipitation were used to examine protein expression and protein-protein interaction. [Cl(-)]iwas measured using 6-methoxy-N-ethylquinolinium iodide dye. The results showed that [Cl(-)]iwas decreased in monocytes/macrophages from patients with hypercholesterolemia and from apoE(-/-)mice fed with a high-fat diet. Lowering [Cl(-)]iupregulated scavenger receptor A (SR-A) expression, increased the binding and uptake of oxLDL, enhanced pro-inflammatory cytokine production and subsequently accelerated foam cell formation in macrophages from humans and mice. In addition, low Cl(-)solution stimulated the activation of JNK and p38 mitogen-activated protein kinases. Inhibition of JNK and p38 blocked Cl(-)reduced medium-induced SR-A expression and lipid accumulation. In contrast, reduction of [Cl(-)]ipromoted the interaction of SR-A with caveolin-1, thus facilitating caveolin-1-dependent SR-A endocytosis. Moreover, disruption of caveolae attenuated SR-A internalization, JNK and p38 activation, and ultimately prevented SR-A expression and foam cell formation stimulated by low Cl(-)medium.
  
  
  CONCLUSIONS
  This data provide strong evidence that reduction of [Cl(-)]iis a critical contributor to intracellular lipid accumulation, suggesting that modulation of [Cl(-)]iis a novel avenue to prevent foam cell formation and atherosclerosis.
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine.
authors.forename: Qian-Qian
authors.initials: QQ
authors.lastname: Wu
authors.forename: Xiao-Yun
authors.initials: XY
authors.lastname: Liu
authors.forename: Li-Xiong
authors.initials: LX
authors.lastname: Xiong
authors.forename: Jin-Yan
authors.initials: JY
authors.lastname: Shang
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Mai
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Pang
authors.forename: Ying-Xue
authors.initials: YX
authors.lastname: Su
authors.forename: Bei-Xin
authors.initials: BX
authors.lastname: Yu
authors.forename: Jia-Ni
authors.initials: JN
authors.lastname: Yuan
authors.forename: Chao
authors.initials: C
authors.lastname: Yang
authors.forename: Yan-Li
authors.initials: YL
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Lv
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Jia-Guo
authors.initials: JG
authors.lastname: Zhou
authors.forename: Si-Jia
authors.initials: SJ
authors.lastname: Liang
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology; D006937:Hypercholesterolemia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051117:Scavenger Receptors, Class A / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D051242:Caveolin 1; D002712:Chlorides; D004041:Dietary Fats; D051117:Scavenger Receptors, Class A; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4