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Increased intracellular Cl concentration mediates neutrophil extracellular traps formation in atherosclerotic cardiovascular diseases

  
@article{APS10707,
	author = {Hui Han and Chang Liu and Mei Li and Jin Wang and Yao-sheng Liu and Yi Zhou and Zi-cheng Li and Rui Hu and Zhi-hong Li and Ruo-mei Wang and Yong-yuan Guan and Bin Zhang and Guan-lei Wang},
	title = {Increased intracellular Cl− concentration mediates neutrophil extracellular traps formation in atherosclerotic cardiovascular diseases},
	journal = {Acta Pharmacologica Sinica},
	volume = {43},
	number = {11},
	year = {2022},
	keywords = {},
	abstract = {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−]i regulated 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−]i by 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.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/10707}
}