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- Title
Extracellular HMGB1 Contributes to the Chronic Cardiac Allograft Vasculopathy/Fibrosis by Modulating TGF-β1 Signaling.
- Authors
Zou, Huijuan; Ming, Bingxia; Li, Jun; Xiao, Yifan; Lai, Lin; Gao, Ming; Xu, Yong; Tan, Zheng; Gong, Feili; Zheng, Fang
- Abstract
Cardiac allograft vasculopathy (CAV) charactered with aberrant remodeling and fibrosis usually leads to the loss of graft after heart transplantation. Our previous work has reported that extracellular high-mobility group box 1 (HMGB1) participated in the CAV progression via promoting inflammatory cells infiltration and immune damage. The aim of this study was to investigate the involvement of HMGB1 in the pathogenesis of CAV/fibrosis and potential mechanisms using a chronic cardiac rejection model in mice. We found high levels of transforming growth factor (TGF)-β1 in cardiac allografts after transplantation. Treatment with HMGB1 neutralizing antibody markedly prolonged the allograft survival accompanied by attenuated fibrosis of cardiac allograft, decreased fibroblasts-to-myofibroblasts conversion, and reduced synthesis and release of TGF-β1. In addition, recombinant HMGB1 stimulation promoted release of active TGF-β1 from cardiac fibroblasts and macrophages in vitro , and subsequent phosphorylation of Smad2 and Smad3 which were downstream of TGF-β1 signaling. These data indicate that HMGB1 contributes to the CAV/fibrosis via promoting the activation of TGF-β1/Smad signaling. Targeting HMGB1 might become a new therapeutic strategy for inhibiting cardiac allograft fibrosis and dysfunction.
- Subjects
FIBROSIS; TRANSFORMING growth factors; HEART transplantation; HEART fibrosis; CARDIAC patients
- Publication
Frontiers in Immunology, 2021, Vol 11, pN.PAG
- ISSN
1664-3224
- Publication type
Article
- DOI
10.3389/fimmu.2021.641973