title: Role of KCa3.1 Channels in Macrophage Polarization and Its Relevance in Atherosclerotic Plaque Instability.
abstract: OBJECTIVE
  Emerging evidence indicates that proinflammatory macrophage polarization imbalance plays a key role in atherosclerotic plaque progression and instability. The calcium-activated potassium channel KCa3.1 is critically involved in macrophage activation and function. However, the role of KCa3.1 in macrophage polarization is unknown. This study investigates the potential role of KCa3.1 in transcriptional regulation in macrophage polarization and its relationship to plaque instability.
  
  
  RESULTS
  Human monocytes were differentiated into macrophages using macrophage colony-stimulating factor. Macrophages were then polarized into proinflammatory M1 cells by interferon-γ and lipopolysaccharide and into alternative M2 macrophages by interleukin-4. A model for plaque instability was induced by combined partial ligation of the left renal artery and left common carotid artery in apolipoprotein E knockout mice. Significant upregulation of KCa3.1 expression was observed during the differentiation of human monocytes into macrophages. Blocking KCa3.1 significantly reduced the expression of proinflammatory genes during macrophages polarization. Further mechanistic studies indicated that blocking KCa3.1 inhibited macrophage differentiation toward the M1 phenotype by downregulating signal transducer and activator of transcription-1 phosphorylation. In animal models, KCa3.1 blockade therapy strikingly reduced the incidence of plaque rupture and luminal thrombus in carotid arteries, decreased the expression of markers associated with M1 macrophage polarization, and enhanced the expression of M2 markers within atherosclerotic lesions.
  
  
  CONCLUSIONS
  These results suggest that blocking KCa3.1 suppresses plaque instability in advanced stages of atherosclerosis by inhibiting macrophage polarization toward an M1 phenotype.
authors.affiliation: From the Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Rende
authors.initials: R
authors.lastname: Xu
authors.affiliation: From the Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Li
authors.affiliation: From the Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Yizhe
authors.initials: Y
authors.lastname: Wu
authors.affiliation: From the Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: From the Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Jianying
authors.initials: J
authors.lastname: Ma
authors.affiliation: From the Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Juying
authors.initials: J
authors.lastname: Qian
authors.affiliation: From the Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China. jbge@zs-hospital.sh.cn qian.juying@zs-hospital.sh.cn.
authors.forename: Junbo
authors.initials: J
authors.lastname: Ge
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D020022:Genetic Predisposition to Disease; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010766:Phosphorylation; D058226:Plaque, Atherosclerotic; D026902:Potassium Channel Blockers / Q000494:pharmacology; D034622:RNA Interference; D012422:Rupture, Spontaneous; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: D001057:Apolipoproteins E; D018836:Inflammation Mediators; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; C496925:Kcnn4 protein, mouse; D008070:Lipopolysaccharides; D026902:Potassium Channel Blockers; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015847:Interleukin-4; D007371:Interferon-gamma
keywords: KCa3.1 channel; apolipoprotein; atherosclerosis; macrophage polarization; plaque instability