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

   
@article{APS10687,
	author = {Han-yan Yang and Chao Zhang and Liang Hu and Chang Liu and Ni Pan and Mei Li and Hui Han and Yi Zhou and Jie Li and Li-yan Zhao and Yao-sheng Liu and Bing-zheng Luo and Xiong-qing Huang and Xiao-fei Lv and Zi-cheng Li and Jun Li and Zhi-hong Li and Ruo-mei Wang and Li Wang and Yong-yuan Guan and Can-zhao Liu and Bin Zhang and Guan-lei Wang},
	title = {Platelet CFTR inhibition enhances arterial thrombosis via increasing intracellular Cl− concentration and activation of SGK1 signaling pathway},
	journal = {Acta Pharmacologica Sinica},
	volume = {43},
	number = {10},
	year = {2022},
	keywords = {},
	abstract = {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 S422D 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 platelet activation in CAD.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/10687}
}