PMID- 36700213
OWN - NLM
STAT- MEDLINE
DCOM- 20230130
LR  - 20230202
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 13
DP  - 2022
TI  - The role of FOXO4/NFAT2 signaling pathway in dysfunction of human coronary 
      endothelial cells and inflammatory infiltration of vasculitis in Kawasaki 
      disease.
PG  - 1090056
LID - 10.3389/fimmu.2022.1090056 [doi]
LID - 1090056
AB  - AIMS: The Ca+/NFAT (Nuclear factor of activated T cells) signaling pathway 
      activation is implicated in the pathogenesis of Kawasaki disease (KD); however, 
      we lack detailed information regarding the regulatory network involved in the 
      human coronary endothelial cell dysfunction and cardiovascular lesion 
      development. Herein, we aimed to use mouse and endothelial cell models of KD 
      vasculitis in vivo and in vitro to characterize the regulatory network of NFAT 
      pathway in KD. METHODS AND RESULTS: Among the NFAT gene family, NFAT2 showed the 
      strongest transcriptional activity in peripheral blood mononuclear cells (PBMCs) 
      from patients with KD. Then, NFAT2 overexpression and knockdown experiments in 
      Human coronary artery endothelial cells (HCAECs) indicated that NFAT2 
      overexpression disrupted endothelial cell homeostasis by regulation of adherens 
      junctions, whereas its knockdown protected HCAECs from such dysfunction. Combined 
      analysis using RNA-sequencing and transcription factor (TF) binding site analysis 
      in the NFAT2 promoter region predicted regulation by Forkhead box O4 (FOXO4). 
      Western blotting, chromatin immunoprecipitation, and luciferase assays validated 
      that FOXO4 binds to the promoter and transcriptionally represses NFAT2. Moreover, 
      Foxo4 knockout increased the extent of inflamed vascular tissues in a mouse model 
      of KD vasculitis. Functional experiments showed that inhibition NFAT2 relieved 
      Foxo4 knockout exaggerated vasculitis in vivo. CONCLUSIONS: Our findings revealed 
      the FOXO4/NFAT2 axis as a vital pathway in the progression of KD that is 
      associated with endothelial cell homeostasis and cardiovascular inflammation 
      development.
CI  - Copyright (c) 2023 Huang, Dong, Jiang, Yang, Zheng, Wang, Wang, Ma, Hou, Ding, 
      Meng, Zhuo, Yang, Qian, Chen, You, Qian, Gu and Lv.
FAU - Huang, Hongbiao
AU  - Huang H
AD  - Department of Pediatrics, Institute of Pediatric Research, Children's Hospital of 
      Soochow University, Suzhou, Jiangsu, China.
AD  - Department of Pediatrics, Fujian Provincial Hospital, Fujian Provincial Clinical 
      College of Fujian Medical University, Fuzhou, Fujian, China.
AD  - Epigenetics Laboratory, Max Planck Institute for Heart and Lung Research, Bad 
      Nauheim, Germany.
FAU - Dong, Jinfeng
AU  - Dong J
AD  - Department of Hematology, the First Affiliated Hospital of Fujian Medical 
      University, Fuzhou, Fujian, China.
FAU - Jiang, Jiaqi
AU  - Jiang J
AD  - Department of Pediatrics, Institute of Pediatric Research, Children's Hospital of 
      Soochow University, Suzhou, Jiangsu, China.
FAU - Yang, Fang
AU  - Yang F
AD  - Department of Pediatrics, Fujian Provincial Hospital, Fujian Provincial Clinical 
      College of Fujian Medical University, Fuzhou, Fujian, China.
FAU - Zheng, Yiming
AU  - Zheng Y
AD  - Department of Pediatrics, Institute of Pediatric Research, Children's Hospital of 
      Soochow University, Suzhou, Jiangsu, China.
FAU - Wang, Shuhui
AU  - Wang S
AD  - Department of Pediatrics, Institute of Pediatric Research, Children's Hospital of 
      Soochow University, Suzhou, Jiangsu, China.
FAU - Wang, Nana
AU  - Wang N
AD  - Department of Pediatrics, Institute of Pediatric Research, Children's Hospital of 
      Soochow University, Suzhou, Jiangsu, China.
FAU - Ma, Jin
AU  - Ma J
AD  - Department of Pediatrics, Institute of Pediatric Research, Children's Hospital of 
      Soochow University, Suzhou, Jiangsu, China.
FAU - Hou, Miao
AU  - Hou M
AD  - Department of Pediatrics, Institute of Pediatric Research, Children's Hospital of 
      Soochow University, Suzhou, Jiangsu, China.
FAU - Ding, Yueyue
AU  - Ding Y
AD  - Department of Pediatrics, Institute of Pediatric Research, Children's Hospital of 
      Soochow University, Suzhou, Jiangsu, China.
FAU - Meng, Lijun
AU  - Meng L
AD  - Department of Hematology, Children's Hospital of Soochow University, Suzhou, 
      China.
FAU - Zhuo, Wenyu
AU  - Zhuo W
AD  - Department of Pediatrics, Institute of Pediatric Research, Children's Hospital of 
      Soochow University, Suzhou, Jiangsu, China.
FAU - Yang, Daoping
AU  - Yang D
AD  - Department of Pediatrics, Institute of Pediatric Research, Children's Hospital of 
      Soochow University, Suzhou, Jiangsu, China.
FAU - Qian, Weiguo
AU  - Qian W
AD  - Department of Pediatrics, Institute of Pediatric Research, Children's Hospital of 
      Soochow University, Suzhou, Jiangsu, China.
FAU - Chen, Qiaobin
AU  - Chen Q
AD  - Department of Pediatrics, Fujian Provincial Hospital, Fujian Provincial Clinical 
      College of Fujian Medical University, Fuzhou, Fujian, China.
FAU - You, Guoping
AU  - You G
AD  - Department of Emergency, Fujian Provincial Hospital, Fujian Provincial Clinical 
      College of Fujian Medical University, Fuzhou, Fujian, China.
FAU - Qian, Guanghui
AU  - Qian G
AD  - Department of Pediatrics, Institute of Pediatric Research, Children's Hospital of 
      Soochow University, Suzhou, Jiangsu, China.
FAU - Gu, Lei
AU  - Gu L
AD  - Epigenetics Laboratory, Max Planck Institute for Heart and Lung Research, Bad 
      Nauheim, Germany.
AD  - Cardiopulmonary Institute (CPI), Bad Nauheim, Germany.
FAU - Lv, Haitao
AU  - Lv H
AD  - Department of Pediatrics, Institute of Pediatric Research, Children's Hospital of 
      Soochow University, Suzhou, Jiangsu, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230109
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (FOXO4 protein, human)
RN  - 0 (FoxO4 protein, mouse)
RN  - 0 (NFATC Transcription Factors)
RN  - 0 (NFATC1 protein, human)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - Cell Cycle Proteins/metabolism
MH  - Endothelial Cells/metabolism
MH  - *Forkhead Transcription Factors/genetics/metabolism
MH  - Leukocytes, Mononuclear/metabolism
MH  - *Mucocutaneous Lymph Node Syndrome/pathology
MH  - *NFATC Transcription Factors/genetics/metabolism
MH  - Signal Transduction
PMC - PMC9869249
OTO - NOTNLM
OT  - Ca+/NFAT pathway
OT  - FOXO4
OT  - Kawasaki disease
OT  - transcription factor
OT  - vasculitis
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2023/01/27 06:00
MHDA- 2023/01/28 06:00
PMCR- 2022/01/01
CRDT- 2023/01/26 02:55
PHST- 2022/11/04 00:00 [received]
PHST- 2022/12/19 00:00 [accepted]
PHST- 2023/01/26 02:55 [entrez]
PHST- 2023/01/27 06:00 [pubmed]
PHST- 2023/01/28 06:00 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2022.1090056 [doi]
PST - epublish
SO  - Front Immunol. 2023 Jan 9;13:1090056. doi: 10.3389/fimmu.2022.1090056. 
      eCollection 2022.