Decrease of Intracellular Chloride Concentration Promotes Endothelial Cell Inflammation by Activating Nuclear Factor-κB Pathway
Hui YangFrom the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center (H.Y., L.-Y.H., D.-Y.Z., E-W.H., S.-J.L., Y.-B.T., Y.-X.S., J.T., F.S., Q.-Q.W., L.-X.X., X.-F.L., J.L., Y.-Y.G., J.-G.Z.), and Department of Forensic Pathology (E.-W.H.), Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Cardiovascular Institute of Guangdong Academy of Medical Sciences, Medical Research Center of Guangdong General Hospital, Guangzhou, China (H.Y.); Guangzhou Forensic ScienceLinyan HuangFrom the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center (H.Y., L.-Y.H., D.-Y.Z., E-W.H., S.-J.L., Y.-B.T., Y.-X.S., J.T., F.S., Q.-Q.W., L.-X.X., X.-F.L., J.L., Y.-Y.G., J.-G.Z.), and Department of Forensic Pathology (E.-W.H.), Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Cardiovascular Institute of Guangdong Academy of Medical Sciences, Medical Research Center of Guangdong General Hospital, Guangzhou, China (H.Y.); Guangzhou Forensic ScienceDe-Yi ZengFrom the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center (H.Y., L.-Y.H., D.-Y.Z., E-W.H., S.-J.L., Y.-B.T., Y.-X.S., J.T., F.S., Q.-Q.W., L.-X.X., X.-F.L., J.L., Y.-Y.G., J.-G.Z.), and Department of Forensic Pathology (E.-W.H.), Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Cardiovascular Institute of Guangdong Academy of Medical Sciences, Medical Research Center of Guangdong General Hospital, Guangzhou, China (H.Y.); Guangzhou Forensic ScienceErwen HuangFrom the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center (H.Y., L.-Y.H., D.-Y.Z., E-W.H., S.-J.L., Y.-B.T., Y.-X.S., J.T., F.S., Q.-Q.W., L.-X.X., X.-F.L., J.L., Y.-Y.G., J.-G.Z.), and Department of Forensic Pathology (E.-W.H.), Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Cardiovascular Institute of Guangdong Academy of Medical Sciences, Medical Research Center of Guangdong General Hospital, Guangzhou, China (H.Y.); Guangzhou Forensic ScienceSijia LiangFrom the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center (H.Y., L.-Y.H., D.-Y.Z., E-W.H., S.-J.L., Y.-B.T., Y.-X.S., J.T., F.S., Q.-Q.W., L.-X.X., X.-F.L., J.L., Y.-Y.G., J.-G.Z.), and Department of Forensic Pathology (E.-W.H.), Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Cardiovascular Institute of Guangdong Academy of Medical Sciences, Medical Research Center of Guangdong General Hospital, Guangzhou, China (H.Y.); Guangzhou Forensic ScienceYong‐Bo TangFrom the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center (H.Y., L.-Y.H., D.-Y.Z., E-W.H., S.-J.L., Y.-B.T., Y.-X.S., J.T., F.S., Q.-Q.W., L.-X.X., X.-F.L., J.L., Y.-Y.G., J.-G.Z.), and Department of Forensic Pathology (E.-W.H.), Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Cardiovascular Institute of Guangdong Academy of Medical Sciences, Medical Research Center of Guangdong General Hospital, Guangzhou, China (H.Y.); Guangzhou Forensic ScienceYing-Xue SuFrom the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center (H.Y., L.-Y.H., D.-Y.Z., E-W.H., S.-J.L., Y.-B.T., Y.-X.S., J.T., F.S., Q.-Q.W., L.-X.X., X.-F.L., J.L., Y.-Y.G., J.-G.Z.), and Department of Forensic Pathology (E.-W.H.), Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Cardiovascular Institute of Guangdong Academy of Medical Sciences, Medical Research Center of Guangdong General Hospital, Guangzhou, China (H.Y.); Guangzhou Forensic ScienceJing TaoFrom the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center (H.Y., L.-Y.H., D.-Y.Z., E-W.H., S.-J.L., Y.-B.T., Y.-X.S., J.T., F.S., Q.-Q.W., L.-X.X., X.-F.L., J.L., Y.-Y.G., J.-G.Z.), and Department of Forensic Pathology (E.-W.H.), Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Cardiovascular Institute of Guangdong Academy of Medical Sciences, Medical Research Center of Guangdong General Hospital, Guangzhou, China (H.Y.); Guangzhou Forensic ScienceFei ShangFrom the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center (H.Y., L.-Y.H., D.-Y.Z., E-W.H., S.-J.L., Y.-B.T., Y.-X.S., J.T., F.S., Q.-Q.W., L.-X.X., X.-F.L., J.L., Y.-Y.G., J.-G.Z.), and Department of Forensic Pathology (E.-W.H.), Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Cardiovascular Institute of Guangdong Academy of Medical Sciences, Medical Research Center of Guangdong General Hospital, Guangzhou, China (H.Y.); Guangzhou Forensic ScienceQianqian WuFrom the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center (H.Y., L.-Y.H., D.-Y.Z., E-W.H., S.-J.L., Y.-B.T., Y.-X.S., J.T., F.S., Q.-Q.W., L.-X.X., X.-F.L., J.L., Y.-Y.G., J.-G.Z.), and Department of Forensic Pathology (E.-W.H.), Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Cardiovascular Institute of Guangdong Academy of Medical Sciences, Medical Research Center of Guangdong General Hospital, Guangzhou, China (H.Y.); Guangzhou Forensic ScienceLi-Xiong XiongFrom the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center (H.Y., L.-Y.H., D.-Y.Z., E-W.H., S.-J.L., Y.-B.T., Y.-X.S., J.T., F.S., Q.-Q.W., L.-X.X., X.-F.L., J.L., Y.-Y.G., J.-G.Z.), and Department of Forensic Pathology (E.-W.H.), Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Cardiovascular Institute of Guangdong Academy of Medical Sciences, Medical Research Center of Guangdong General Hospital, Guangzhou, China (H.Y.); Guangzhou Forensic ScienceXiaofei LvFrom the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center (H.Y., L.-Y.H., D.-Y.Z., E-W.H., S.-J.L., Y.-B.T., Y.-X.S., J.T., F.S., Q.-Q.W., L.-X.X., X.-F.L., J.L., Y.-Y.G., J.-G.Z.), and Department of Forensic Pathology (E.-W.H.), Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Cardiovascular Institute of Guangdong Academy of Medical Sciences, Medical Research Center of Guangdong General Hospital, Guangzhou, China (H.Y.); Guangzhou Forensic ScienceJie LiuFrom the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center (H.Y., L.-Y.H., D.-Y.Z., E-W.H., S.-J.L., Y.-B.T., Y.-X.S., J.T., F.S., Q.-Q.W., L.-X.X., X.-F.L., J.L., Y.-Y.G., J.-G.Z.), and Department of Forensic Pathology (E.-W.H.), Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Cardiovascular Institute of Guangdong Academy of Medical Sciences, Medical Research Center of Guangdong General Hospital, Guangzhou, China (H.Y.); Guangzhou Forensic ScienceYong‐Yuan GuanFrom the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center (H.Y., L.-Y.H., D.-Y.Z., E-W.H., S.-J.L., Y.-B.T., Y.-X.S., J.T., F.S., Q.-Q.W., L.-X.X., X.-F.L., J.L., Y.-Y.G., J.-G.Z.), and Department of Forensic Pathology (E.-W.H.), Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Cardiovascular Institute of Guangdong Academy of Medical Sciences, Medical Research Center of Guangdong General Hospital, Guangzhou, China (H.Y.); Guangzhou Forensic ScienceJia‐Guo ZhouFrom the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center (H.Y., L.-Y.H., D.-Y.Z., E-W.H., S.-J.L., Y.-B.T., Y.-X.S., J.T., F.S., Q.-Q.W., L.-X.X., X.-F.L., J.L., Y.-Y.G., J.-G.Z.), and Department of Forensic Pathology (E.-W.H.), Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Cardiovascular Institute of Guangdong Academy of Medical Sciences, Medical Research Center of Guangdong General Hospital, Guangzhou, China (H.Y.); Guangzhou Forensic Science
2012en
ABI
Abstract
Recent evidence suggested that ClC-3 channel/antiporter is involved in regulation of nuclear factor (NF)-κB activation. However, the mechanism explaining how ClC-3 modulates NF-κB 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-κB activity in endothelial cells. Here, we found that reduction of [Cl(-)](i) increased tumor necrosis factor-α (TNFα)-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, TNFα-evoked IκB kinase complex β and inhibitors of κBα phosphorylation, inhibitors of κBα degradation, and NF-κB nuclear translocation were enhanced. In addition, TNFα and interleukin 1β 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 TNFα-induced intercellular adhesion molecule 1 and vascular cell adhesion molecule 1expression, monocytes to endothelial cell adhesion, and NF-κB activation (P<0.01; n=6). Furthermore, TNFα-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-κB activation and thus potentiates TNFα-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.
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