Causal Role for Neutrophil Elastase in Thoracic Aortic Dissection in Mice

作者全名："Yang, Mei; Zhou, Xinmiao; Pearce, Stuart W. A.; Yang, Zhisheng; Chen, Qishan; Niu, Kaiyuan; Liu, Chenxin; Luo, Jun; Li, Dan; Shao, Yue; Zhang, Cheng; Chen, Dan; Wu, Qingchen; Cutillas, Pedro R.; Zhao, Lin; Xiao, Qingzhong; Zhang, Li"

作者地址："[Zhang, Li] Shanghai Jiao Tong Univ, Xinhua Hosp, Inst Dev & Regenerat Cardiovasc Med, Dept Cardiol,Sch Med, Shanghai 200092, Peoples R China; [Xiao, Qingzhong] Queen Mary Univ London, William Harvey Res Inst, Fac Med & Dent, Ctr Clin Pharmacol,Heart Ctr, Charterhouse Sq, London EC1M 6BQ, England; [Yang, Mei; Chen, Qishan; Li, Dan; Zhang, Li] Shanghai Jiao Tong Univ, Xinhua Hosp, Inst Dev & Regenerat Cardiovasc Med, Sch Med,Dept Cardiol, Shanghai, Peoples R China; [Yang, Mei; Zhou, Xinmiao; Pearce, Stuart W. A.; Yang, Zhisheng; Niu, Kaiyuan; Liu, Chenxin; Xiao, Qingzhong] Queen Mary Univ London, Fac Med & Dent, William Harvey Res Inst, London, England; [Cutillas, Pedro R.] Queen Mary Univ London, Barts Canc Inst, Fac Med & Dent, Ctr Haemato Oncol, London, England; [Zhou, Xinmiao] Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Resp & Crit Care Med, Sch Med, Hangzhou, Peoples R China; [Luo, Jun; Shao, Yue; Zhang, Cheng; Chen, Dan; Wu, Qingchen] Chongqing Med Univ, Affiliated Hosp 1, Dept Cardiothorac Surg, Chongqing, Peoples R China; [Li, Dan; Zhao, Lin] Capital Med Univ, Beijing Anzhen Hosp, Dept Cardiol, Beijing, Peoples R China; [Xiao, Qingzhong] Guangzhou Med Univ, Affiliated Hosp 2, Sch Basic Med Sci, Guangzhou Inst Cardiovasc Dis,Key Lab Cardiovasc D, Guangzhou, Peoples R China"

通信作者："Zhang, L (通讯作者)，Shanghai Jiao Tong Univ, Xinhua Hosp, Inst Dev & Regenerat Cardiovasc Med, Dept Cardiol,Sch Med, Shanghai 200092, Peoples R China.; Xiao, QZ (通讯作者)，Queen Mary Univ London, William Harvey Res Inst, Fac Med & Dent, Ctr Clin Pharmacol,Heart Ctr, Charterhouse Sq, London EC1M 6BQ, England.; Zhao, L (通讯作者)，Capital Med Univ, Beijing Anzhen Hosp, Dept Cardiol, Beijing, Peoples R China."

来源：ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001073432300017

JCR分区：Q1

影响因子：8.7

年份：2023

卷号：43

期号：10

开始页：1900

结束页：1920

文献类型：Article

关键词："dissection, thoracic aorta; extracellular traps; inflammation; leukocyte elastase; phenotype"

摘要："BACKGROUND:Thoracic aortic dissection (TAD) is a life-threatening aortic disease without effective medical treatment. Increasing evidence has suggested a role for NE (neutrophil elastase) in vascular diseases. In this study, we aimed at investigating a causal role for NE in TAD and exploring the molecular mechanisms involved.METHODS:& beta;-aminopropionitrile monofumarate was administrated in mice to induce TAD. NE deficiency mice, pharmacological inhibitor GW311616A, and adeno-associated virus-2-mediated in vivo gene transfer were applied to explore a causal role for NE and associated target gene in TAD formation. Multiple functional assays and biochemical analyses were conducted to unravel the underlying cellular and molecular mechanisms of NE in TAD.RESULTS:NE aortic gene expression and plasma activity was significantly increased during & beta;-aminopropionitrile monofumarate-induced TAD and in patients with acute TAD. NE deficiency prevents & beta;-aminopropionitrile monofumarate-induced TAD onset/development, and GW311616A administration ameliorated TAD formation/progression. Decreased levels of neutrophil extracellular traps, inflammatory cells, and MMP (matrix metalloproteinase)-2/9 were observed in NE-deficient mice. TBL1x (F-box-like/WD repeat-containing protein TBL1x) has been identified as a novel substrate and functional downstream target of NE in TAD. Loss-of-function studies revealed that NE mediated inflammatory cell transendothelial migration by modulating TBL1x-LTA4H (leukotriene A4 hydrolase) signaling and that NE regulated smooth muscle cell phenotype modulation under TAD pathological condition by regulating TBL1x-MECP2 (methyl CpG-binding protein 2) signal axis. Further mechanistic studies showed that TBL1x inhibition decreased the binding of TBL1x and HDAC3 (histone deacetylase 3) to MECP2 and LTA4H gene promoters, respectively. Finally, adeno-associated virus-2-mediated Tbl1x gene knockdown in aortic smooth muscle cells confirmed a regulatory role for TBL1x in NE-mediated TAD formation.CONCLUSIONS:We unravel a critical role of NE and its target TBL1x in regulating inflammatory cell migration and smooth muscle cell phenotype modulation in the context of TAD. Our findings suggest that the NE-TBL1x signal axis represents a valuable therapeutic for treating high-risk TAD patients."

基金机构："National Key R&D Program of China [2022YFA1104200]; British Heart Foundation [PG/15/11/31279, PG/15/86/31723, PG/16/1/31892, PG/20/10458, PG/23/11371]; National Natural Sciences Foundation of China [82125005, 82100503, 81800364, 81930010, 81870206]; Shanghai Shenkang Three-Year Action Plan for Promoting Clinical Skills and Clinical Innovation in Municipal Hospitals [SHDC2020CR4015]"

基金资助正文："This work was partially supported by National Key R&D Program of China (2022YFA1104200), the British Heart Foundation (PG/15/11/31279, PG/15/86/31723, PG/16/1/31892, PG/20/10458, and PG/23/11371), National Natural Sciences Foundation of China (82125005, 82100503, 81800364, 81930010, and 81870206), and Shanghai Shenkang Three-Year Action Plan for Promoting Clinical Skills and Clinical Innovation in Municipal Hospitals (SHDC2020CR4015). This work forms part of the research portfolio for the National Institute for Health Research Biomedical Research Centre at Barts."