Abstract 11257: Hmgb-1 Signal Via Tlr-9 Plays Critical Role iIn Vascular Remodeling
[Background] High-mobility group box-1 (HMGB1) is a highly conserved nuclear protein that modulates chromatin structure. Recent reports suggest that HMGB1 acts as an important mediator in inflammatory disorders such as sepsis. In addition, the receptors of HMGB1 signal are reported to be Toll-like receptors (TLRs) or receptor for advanced glycation end-products (RAGE). We assessed the hypothesis that HMGB1 plays a critical role in vascular remodeling after endovascular injury via TLR9 pathway.
[Methods and Results] We performed wire-mediated endovascular injury in C57BL/6 (WT) mice. Local and serum HMGB1 levels increased after the injury. Local delivery of a neutralizing anti-HMGB1 antibody into the perivascular area with gelatin-hydrogel significantly attenuated neointimal hyperplasia at 4 weeks after the injury compared with the PBS delivery (p<0.05). These results suggest that HMGB1 acts as a chronic inflammatory mediator in vascular remodeling. Next, we delivered HMGB1 protein around the injured arteries with gelatin-hydrogel in WT and TLR9 KO mice. Neointima formation was exacerbated by the HMGB1 treatment in WT mice, whereas HMGB1 treatment had no effect in TLR9 KO mice. These results suggest that TLR9 plays a pivotal role in pathway of HMGB1 signal. To evaluate the involvement of bone marrow derived cells to neointima formation, we performed bone marrow transplantation between TLR9-KO and WT mice. Neointimal formation was attenuated in “KO to WT” mice compared to “WT to WT” mice (p<0.05), whereas there was no difference between “WT to KO” and “KO to KO” mice. These results suggest that TLR9 in bone marrow derived cells play a critical role in vascular remodeling. In vitro study, rat smooth muscle cells (SMCs), mouse macrophages (RAW 264.7) and human endothelial cells (HUVECs) were cultured with LPS for 24 hoursHMGB1 level was elevated in the medium of macrophages in time dependent manner, but was not changed in SMCs and HUVECs. These findings suggest that HMGB1 was not only secreted from necrotic cells, but also secreted from macrophages.
[Conclusions] Our findings suggest that HMGB1 signal via TLR9 may play a critical role in vascular remodeling.
- © 2011 by American Heart Association, Inc.