Abstract
Vascular smooth muscle cells (VSMCs) are the major cell type in the blood vessel walls, and their phenotypic modulation is a key cellular event driving vascular remodeling. Although high mobility group box-1 (HMGB1) plays a pivotal role in inflammatory processes after vascular injuries, the importance of the links between VSMCs, HMGB1 and vascular inflammation has not been clarified. To prove the hypothesis that VSMCs might be active players in vascular inflammation by secreting inflammatory cytokines, we investigated the proinflammatory effects of HMGB1 and its intermediary signaling pathways in VSMCs. When cultured human VSMCs were stimulated with HMGB1 (10–500 ng/ml), IL-1β production was markedly increased. HMGB1 also increased the expression of NLRP3 inflammasome components including NLRP3, ASC and caspase-1. Among these components, HMGB1-induced expressions of NLRP3 and caspase-1 were markedly attenuated in TLR2 siRNA-transfected cells, whereas ASC and caspase-1 expressions were reduced in RAGE-deficient cells. In TLR4-deficient cells, HMGB1-induced caspase-1 expression was significantly attenuated. Moreover, IL-1β production in HMGB1-stimulated cells was significantly reduced in cells transfected with caspase-1 siRNA as well as in cells treated with monoclonal antibodies or siRNAs for TLR2, TLR4 and RAGE. Overall, this study identified a pivotal role for NLRP3 inflammasome and its receptor signaling involved in the production of IL-1β in VSMCs stimulated with HMGB1. Thus, targeting HMGB1 signaling in VSMCs offers a promising therapeutic strategy for treating vascular remodeling diseases.
Highlights
Vascular inflammation plays an important role in the pathogenesis of vascular diseases, including vascular remodeling and atherosclerosis (Libby, 2002; Davis et al, 2003)
RT-PCR and Western blot analyses indicated that IL-1β mRNA and protein were expressed at low levels in vascular smooth muscle cells (VSMCs) in the absence of high mobility group box-1 (HMGB1) stimulation, but when VSMCs were stimulated with 10–500 ng/ml of HMGB1, both IL-1β mRNA expression and protein production were markedly increased
Previous studies have argued that IL-1β plays a crucial regulatory role in vascular inflammation, but little is known of the role played by VSMCs in damaged vasculatures
Summary
Vascular inflammation plays an important role in the pathogenesis of vascular diseases, including vascular remodeling and atherosclerosis (Libby, 2002; Davis et al, 2003). VSMCs are the major cell type in blood vessel walls and play pivotal roles in vascular disease processes by changing phenotype from the contractile to the synthetic phenotype, the latter exhibits distinct proliferative and migratory abilities and produces proinflammatory cytokines (Wang et al, 2012; Ackers-Johnson et al, 2015). High levels of extracellular HMGB1 have been detected in human atherosclerotic plaque, and reportedly are implicated in vascular inflammation by potentiating inflammatory responses (Kalinina et al, 2004; Cai et al, 2015). It has been shown that HMGB1 modulates the phenotype of VSMCs toward the activated synthetic phenotype and stimulates MCP-1/CCL2 gene expression through toll-like receptor 4 (TLR4) (Cai et al, 2015; Wang et al, 2017). The nature of the links between VSMCs, HMGB1, and vascular inflammation have not been clarified
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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.
