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.
Highlights
Despite considerable advances have been achieved in controlling acute rejection, the longterm survival of cardiac allograft remains limited by chronic rejection which charactered with cardiac allograft vasculopathy (CAV) [1, 2]
To investigate the role of high-mobility group box 1 (HMGB1) in the fibrosis of cardiac allograft, the heart of bm12 mouse was transplanted to the B6 mouse, which was called MHC Class II (MHC-II) mismatched model charactered by chronic allograft fibrosis
In our previous study and other works, it has been reported the involvement of HMGB1 in the development of cardiac allograft rejection via promoting the inflammatory cells infiltration and immune damage [24, 25]
Summary
Despite considerable advances have been achieved in controlling acute rejection, the longterm survival of cardiac allograft remains limited by chronic rejection which charactered with cardiac allograft vasculopathy (CAV) [1, 2]. The distinctive features of CAV are fibroblasts-tomyofibroblasts conversion and deposition of extracellular matrix (ECM), fibrosis around the blood vessels accompanied by inflammatory cells infiltration, and subsequent lumen constriction resulting in ischemic graft failure [2]. Resident cardiac fibroblasts proliferate and develop into matrix-producing α-smooth muscle actin-expressing (α-SMA+) myofibroblasts to produce ECM proteins [4, 5]. This process is often induced by the factor of transforming growth factor (TGF)β1. In acute response to injury, TGF-β1 was primarily released from platelets and T cells, this release is important in macrophage and fibroblast chemotaxis to the injured site [6, 7]. Activated TGF-β1 produced from an inactive precursor is a crucial mediator of fibrotic disorder, which activates TGF-β1 signaling through a classical SMAD pathway [7] or an alternative SMAD independent pathway [8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
