AUTHOR=Huang Hongbiao , Dong Jinfeng , Jiang Jiaqi , Yang Fang , Zheng Yiming , Wang Shuhui , Wang Nana , Ma Jin , Hou Miao , Ding Yueyue , Meng Lijun , Zhuo Wenyu , Yang Daoping , Qian Weiguo , Chen Qiaobin , You Guoping , Qian Guanghui , Gu Lei , Lv Haitao 

TITLE=The role of FOXO4/NFAT2 signaling pathway in dysfunction of human coronary endothelial cells and inflammatory infiltration of vasculitis in Kawasaki disease

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1090056

DOI=10.3389/fimmu.2022.1090056

ISSN=1664-3224

ABSTRACT=<sec><title>Aims</title><p>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 <italic>in vivo</italic> and <italic>in vitro</italic> to characterize the regulatory network of NFAT pathway in KD.</p></sec><sec><title>Methods and Results</title><p>Among the NFAT gene family, <italic>NFAT2</italic> showed the strongest transcriptional activity in peripheral blood mononuclear cells (PBMCs) from patients with KD. Then, <italic>NFAT2</italic> overexpression and knockdown experiments in Human coronary artery endothelial cells (HCAECs) indicated that <italic>NFAT2</italic> 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 <italic>NFAT2</italic> promoter region predicted regulation by Forkhead box O4 (FOXO4). Western blotting, chromatin immunoprecipitation, and luciferase assays validated that <italic>FOXO4</italic> binds to the promoter and transcriptionally represses <italic>NFAT2</italic>. Moreover, <italic>Foxo4</italic> knockout increased the extent of inflamed vascular tissues in a mouse model of KD vasculitis. Functional experiments showed that inhibition NFAT2 relieved <italic>Foxo4</italic> knockout exaggerated vasculitis <italic>in vivo</italic>.</p></sec><sec><title>Conclusions</title><p>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.</p></sec>