Decrease of Intracellular Chloride Concentration Promotes Endothelial Cell Inflammation by Activating Nuclear Factor-κB Pathway

被引：118

作者：

Yang, Hui ^{[1
,3
]}

Huang, Lin-Yan ^{[1
]}

Zeng, De-Yi ^{[1
]}

Huang, Er-Wen ^{[1
,2
,4
]}

Liang, Si-Jia ^{[1
]}

Tang, Yong-Bo ^{[1
]}

Su, Ying-Xue ^{[1
]}

Tao, Jing ^{[1
]}

Shang, Fei ^{[1
]}

Wu, Qian-Qian ^{[1
]}

Xiong, Li-Xiong ^{[1
]}

Lv, Xiao-Fei ^{[1
]}

Liu, Jie ^{[1
]}

Guan, Yong-Yuan ^{[1
]}

Zhou, Jia-Guo ^{[1
]}

机构：

[1] Sun Yat Sen Univ, Dept Pharmacol, Cardiac & Cerebral Vasc Res Ctr, Zhongshan Sch Med, Guangzhou 510080, Guangdong, Peoples R China

[2] Sun Yat Sen Univ, Dept Forens Pathol, Zhongshan Sch Med, Guangzhou 510080, Guangdong, Peoples R China

[3] Guangdong Gen Hosp, Cardiovasc Inst, Guangdong Acad Med Sci, Med Res Ctr, Guangzhou 510080, Guangdong, Peoples R China

[4] Guangzhou Forens Sci Inst, Guangzhou 510030, Guangdong, Peoples R China

来源：

HYPERTENSION | 2012年 / 60卷 / 05期

基金：

中国国家自然科学基金;

关键词：

basic science; membrane transport/ion channels; cytokines; endothelium; inflammation; ion channels; SMOOTH-MUSCLE-CELLS; VOLUME REGULATION; CHANNELS; CLC-3; EXPRESSION; PHOSPHORYLATION; TRANSMISSION; APOPTOSIS; PROTEIN;

D O I：

10.1161/HYPERTENSIONAHA.112.198648

中图分类号：

R6 [外科学];

学科分类号：

100210 [外科学];

摘要：

Recent evidence suggested that ClC-3 channel/antiporter is involved in regulation of nuclear factor (NF)-kappa B activation. However, the mechanism explaining how ClC-3 modulates NF-kappa B signaling is not well understood. We hypothesized that ClC-3-dependent alteration of intracellular chloride concentration ([Cl-](i)) underlies the effect of ClC-3 on NF-kappa B activity in endothelial cells. Here, we found that reduction of [Cl-](i) increased tumor necrosis factor-alpha (TNF alpha)-induced expression of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 and adhesion of monocytes to endothelial cells (P<0.05; n=6). In Cl- reduced solutions, TNF alpha-evoked I kappa B kinase complex beta and inhibitors of kappa B alpha phosphorylation, inhibitors of kappa B alpha degradation, and NF-kappa B nuclear translocation were enhanced. In addition, TNF alpha and interleukin 1 beta could activate an outward rectifying Cl- current in human umbilical vein endothelial cells and mouse aortic endothelial cells. Knockdown or genetic deletion of ClC-3 inhibited or abolished this Cl- conductance. Moreover, Cl- channel blockers, ClC-3 knockdown or knockout remarkably reduced TNF alpha-induced intercellular adhesion molecule 1 and vascular cell adhesion molecule 1expression, monocytes to endothelial cell adhesion, and NF-kappa B activation (P<0.01; n=6). Furthermore, TNF alpha-induced vascular inflammation and neutrophil infiltration into the lung and liver were obviously attenuated in ClC-3 knockout mice (P<0.01; n=7). Our results demonstrated that decrease of [Cl-](i) induced by ClC-3-dependent Cl- efflux promotes NF-kappa B activation and thus potentiates TNF alpha-induced vascular inflammation, suggesting that inhibition of ClC-3-dependent Cl- current or modification of intracellular Cl- content may be a novel therapeutic approach for inflammatory diseases. (Hypertension. 2012;60:1287-1293.)

引用

页码：1287 / +

页数：25

共 37 条

[1]

Secretion and cell volume regulation by salivary acinar cells from mice lacking expression of the Clcn3 Cl- channel gene [J].