Neutrophil extracellular traps(NETs)play crucial roles in atherosclerotic cardiovascular diseases such as acute coronary syndrome(ACS).Our preliminary study shows that oxidized low-density lipoprotein(oxLDL)-induced NET formation is accompanied by an elevated intracellular Cl-concentration([Cl-]i)and reduced cystic fibrosis transmembrane conductance regulator(CFTR)expression in freshly isolated human blood neutrophils.Herein we investigated whether and how[Cl-]iregulated NET formation in vitro and in vivo.We showed that neutrophil[Cl-]i and NET levels were increased in global CFTR null(Cftr-/-)mice in the resting state,which was mimicked by intravenous injection of the CFTR inhibitor,CFTRinh-172,in wild-type mice.OxLDL-induced NET formation was aggravated by defective CFTR function.Clamping[Cl-]i at high levels directly triggered NET formation.Furthermore,we demonstrated that increased[Cl-]iby CFTRinh-172 or CFTR knockout increased the phosphorylation of serum-and glucocorticoid-inducible protein kinase 1(SGK1)and generation of intracellular reactive oxygen species in neutrophils,and promoted oxLDL-induced NET formation and pro-inflammatory cytokine production.Consistently,peripheral blood samples obtained from atherosclerotic ApoE-/-mice or stable angina(SA)and ST-elevation ACS(STE-ACS)patients exhibited increased neutrophil[Cl-]i and SGK1 activity,decreased CFTR expression,and elevated NET levels.VX-661,a CFTR corrector,reduced the NET formation in the peripheral blood sample obtained from oxLDL-injected mice,ApoE-/-atherosclerotic mice or patients with STE-ACS by lowering neutrophil[Cl-]i.These results demonstrate that elevated neutrophil[Cl-]i during the development of atherosclerosis and ACS contributes to increased NET formation via Cl--sensitive SGK1 signaling,suggesting that defective CFTR function might be a novel therapeutic target for atherosclerotic cardiovascular diseases.

Hui Han;Chang Liu;Mei Li;Jin Wang;Yao-sheng Liu;Yi Zhou;Zi-cheng Li;Rui Hu;Zhi-hong Li;Ruo-mei Wang;Yong-yuan Guan;Bin Zhang;Guan-lei Wang

Department of Pharmacology,Cardiac and Cerebral Vascular Research Center,Zhongshan School of Medicine,Sun Yat-sen University,Guangzhou 510080,China;VIP Healthcare Center,the Third Affiliated Hospital of Sun Yat-sen University,Guangzhou 510630,China;Guangdong Cardiovascular Institute,Guangdong Provincial People's Hospital,Guangdong Academy of Medical Sciences,Guangzhou 510080,China;School of Data and Computer Science,Sun Yat-sen University,Guangzhou 510006,China

中国药理学报（英文版）

[1]Hui Han;Chang Liu;Mei Li;Jin Wang;Yao-sheng Liu;Yi Zhou;Zi-cheng Li;Rui Hu;Zhi-hong Li;Ruo-mei Wang;Yong-yuan Guan;Bin Zhang;Guan-lei Wang-.Increased intracellular Cl-concentration mediates neutrophil extracellular traps formation in atherosclerotic cardiovascular diseases)[J].中国药理学报（英文版）,2022(11):2848-2861

iregulated,Cftr,CFTRinh,iby

Increased,intracellular,concentration,mediates,extracellular,traps,formation,atherosclerotic,cardiovascular,diseases,Neutrophil,NETs,play,crucial,roles,such,acute,coronary,syndrome,ACS,Our,preliminary,study,shows,that,oxidized,density,lipoprotein,oxLDL,induced,accompanied,elevated,reduced,cystic,fibrosis,transmembrane,conductance,regulator,expression,freshly,isolated,human,blood,neutrophils,Herein,investigated,whether,vitro,vivo,We,showed,levels,were,increased,global,null,mice,resting,state,which,was,mimicked,intravenous,injection,inhibitor,wild,type,OxLDL,aggravated,defective,function,Clamping,high,directly,triggered,Furthermore,demonstrated,knockout,phosphorylation,serum,glucocorticoid,inducible,kinase,SGK1,generation,reactive,oxygen,species,promoted,inflammatory,cytokine,production,Consistently,peripheral,samples,obtained,from,ApoE,stable,angina,SA,elevation,STE,patients,exhibited,activity,decreased,VX,corrector,injected,lowering,These,results,during,development,atherosclerosis,contributes,via,sensitive,signaling,suggesting,might,be,novel,therapeutic,target

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