Platelet CFTR inhibition enhances arterial thrombosis via increasing intracellular Cl-concentration and activation of SGK1 signaling pathway  

作　　者：Han-yan Yang Chao Zhang Liang Hu Chang Liu Ni Pan Mei Li Hui Han Yi Zhou Jie Li Li-yan Zhao Yao-sheng Liu Bing-zheng Luo Xiong-qing Huang Xiao-fei Lv Zi-cheng Li Jun Li Zhi-hong Li Ruo-mei Wang Li Wang Yong-yuan Guan Can-zhao Liu Bin Zhang Guan-lei Wang 

机构地区：[1]Department of Pharmacology,Zhongshan School of Medicine,Sun Yat-sen University,Guangzhou 510080,China [2]Academy of Integrative Medicine,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China [3]Institute of Pediatrics,Guangzhou Women and Children’s Medical Center affiliated to Guangzhou Medical College,Guangzhou 510623,China [4]VIP Healthcare Center,the Third Affiliated Hospital of Sun Yat-sen University,Guangzhou 510630,China [5]Guangdong Cardiovascular Institute,Guangdong Provincial People’s Hospital,Guangdong Academy of Medical Sciences,Guangzhou 510080,China [6]Department of Anesthesiology,The Second Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou 510120,China [7]Department of Pharmacy,The First Affiliated Hospital of Sun Yat-sen University,Guangzhou 510080,China [8]Department of Anesthesiology,the First Affiliated Hospital,Sun Yat-sen University,Guangzhou 510080,China [9]School of Computer Science and Engineering,Sun Yat-sen University,Guangzhou 510006,China [10]Division of Biological Sciences,University of California,San Diego,La Jolla,CA,USA [11]Department of Cardiovascular Medicine,Translational Medicine Research Center,Zhujiang Hospital,Southern Medical University,Guangzhou 510280,China

出　　处：《Acta Pharmacologica Sinica》2022年第10期2596-2608,共13页中国药理学报（英文版）

基　　金：This study was supported by the National Natural Science Foundation of China(82073848 and 81773722 to GLW,82170231 to CZL,81803522 to LH,81903687 to LYZ,62172452 to RMW,82104160 to NP);The Science and Technology Program of Guangzhou City(No.201803010092 to GLW,China);Guangdong Natural Science Foundation(No.2020A1515010045 to LYZ,China);Guangdong Provincial Department of Science and Technology(No.2017A020215104 to LYZ,China).

摘　　要：Platelet hyperactivity is essential for thrombus formation in coronary artery diseases(CAD).Dysfunction of the cystic fibrosis transmembrane conductance regulator(CFTR)in patients with cystic fibrosis elevates intracellular Cl^(-)levels([Cl^(-)]i)and enhanced platelet hyperactivity.In this study,we explored whether alteration of[Cl^(-)]i has a pathological role in regulating platelet hyperactivity and arterial thrombosis formation.CFTR expression was significantly decreased,while[Cl^(-)]i was increased in platelets from CAD patients.In a FeCl3-induced mouse mesenteric arteriole thrombosis model,platelet-specific Cftr-knockout and/or pre-administration of ion channel inhibitor CFTRinh-172 increased platelet[Cl^(-)]i,which accelerated thrombus formation,enhanced platelet aggregation and ATP release,and increased P2Y12 and PAR4 expression in platelets.Conversely,Cftr-overexpressing platelets resulted in subnormal[Cl^(-)]i,thereby decreasing thrombosis formation.Our results showed that clamping[Cl^(-)]i at high levels or Cftr deficiency-induced[Cl^(-)]i increasement dramatically augmented phosphorylation(Ser422)of serum and glucocorticoid-regulated kinase(SGK1),subsequently upregulated P2Y12 and PAR4 expression via NF-κB signaling.Constitutively active mutant S422^(D)SGK1 markedly increased P2Y12 and PAR4 expression.The specific SGK1 inhibitor GSK-650394 decreased platelet aggregation in wildtype and platelet-specific Cftr knockout mice,and platelet SGK1 phosphorylation was observed in line with increased[Cl^(-)]i and decreased CFTR expression in CAD patients.Co-transfection of S422D SGK1 and adenovirus-induced CFTR overexpression in MEG-01 cells restored platelet activation signaling cascade.Our results suggest that[Cl^(-)]i is a novel positive regulator of platelet activation and arterial thrombus formation via the activation of a[Cl^(-)]i-sensitive SGK1 signaling pathway.Therefore,[Cl^(-)]i in platelets is a novel potential biomarker for platelet hyperactivity,and CFTR may be a potential therapeutic target for pl

关 键 词：coronary artery disease THROMBOSIS PLATELET CFTR intracellular chloride SGK1 

分 类 号：R965[医药卫生—药理学]