Vascular smooth muscle-specific LRRC8A knockout ameliorates angiotensin II-induced cerebrovascular remodeling by inhibiting the WNK1/FOXO3a/MMP signaling pathway  

作　　者：Feng-ting Lu Cheng-cui Huang Wen-yi Lai Gui-yong Yang Zhu-jun Liang Zi-yi Zhang Tanvi Chokshi Kai-min Guo Yu-bo Tang Yuan Chen Zhong-han Yang Si-jia Liang Rui-ping Pang Jia-guo Zhou Yong-yuan Guan Xiao-fei Lv Ming-ming Ma 

机构地区：[1]Department of Pharmacology,and Cardiac&Cerebral Vascular Research Center,Zhongshan School of Medicine,Sun Yat-Sen University,Guangzhou,510080,China [2]Department of Molecular Medicine,School of Medicine,Sun Yat-Sen University,Shenzhen,518107,China [3]Department of Pharmacy,the Sixth Affiliated Hospital,Sun Yat-Sen University,Guangzhou,510655,China [4]Research Division,Joslin Diabetes Center,Harvard University,Boston,MA,USA [5]Department of Obstetrics and Gynecology,Guangzhou Women and Children’s Medical Center,Guangzhou Medical University,Guangzhou,510623,China [6]Department of Pharmacy,The First Affiliated Hospital of Sun Yat-sen University,Guangzhou,510080,China [7]Advanced Medical Technology Center,The First Affiliated Hospital,Zhongshan School of Medicine,Sun Yat-Sen University,Guangzhou,510080,China [8]Department of Physiology,Zhongshan School of Medicine,Sun Yat-Sen University,Guangzhou,510080,China

出　　处：《Acta Pharmacologica Sinica》2024年第9期1848-1860,共13页中国药理学报（英文版）

基　　金：National Natural Science Foundation of China(No.82373866 to MM Ma,No.81773721 to YY Guan,No.81903598 to XF Lv,No.82073839 to SJ Liang,No.82360312 to KM Guo);Natural Science Foundation of Guangdong Province(2021A1515012427 and 2022A1515012471 to MM Ma,2021A1515010378 to XF Lv);Science and Technology Program of Guangzhou(202201020610 to KM Guo);Fundamental Research Funds for the Central Universities,Sun Yat-Sen University(No.22ykqb09 to SJ Liang).

摘　　要：Hypertensive cerebrovascular remodeling involves the enlargement of vascular smooth muscle cells(VSMCs),which activates volume-regulated Cl−channels(VRCCs).The leucine-rich repeat-containing family 8 A(LRRC8A)has been shown to be the molecular identity of VRCCs.However,its role in vascular remodeling during hypertension is unclear.In this study,we used vascular smooth muscle-specific LRRC8A knockout(CKO)mice and an angiotensin II(Ang II)-induced hypertension model.The results showed that cerebrovascular remodeling during hypertension was ameliorated in CKO mice,and extracellular matrix(ECM)deposition was reduced.Based on the RNA-sequencing analysis of aortic tissues,the level of matrix metalloproteinases(MMPs),such as MMP-9 and MMP-14,were reduced in CKO mice with hypertension,which was further verified in vivo by qPCR and immunofluorescence analysis.Knockdown of LRRC8A in VSMCs inhibited the Ang II-induced upregulation of collagen I,fibronectin,and matrix metalloproteinases(MMPs),and overexpression of LRRC8A had the opposite effect.Further experiments revealed an interaction between with-no-lysine(K)-1(WNK1),which is a“Cl−-sensitive kinase”,and Forkhead transcription factor O3a(FOXO3a),which is a transcription factor that regulates MMP expression.Ang II induced the phosphorylation of WNK1 and downstream FOXO3a,which then increased the expression of MMP-2 and MMP-9.This process was inhibited or potentiated when LRRC8A was knocked down or overexpressed,respectively.Overall,these results demonstrate that LRRC8A knockout in vascular smooth muscle protects against cerebrovascular remodeling during hypertension by reducing ECM deposition and inhibiting the WNK1/FOXO3a/MMP signaling pathway,demonstrating that LRRC8A is a potential therapeutic target for vascular remodeling-associated diseases such as stroke.

关 键 词：extracellular matrix FOXO3A LRRC8A matrix metalloproteinases vascular remodeling WNK1 

分 类 号：R54[医药卫生—心血管疾病]