The Role of High Mobility Group Box 1 Protein in Interleukin-18-Induced Myofibroblastic Transition of Valvular Interstitial Cells

Abstract

Background: Increased levels of interleukin-18 (IL-18) and high mobility group box 1 protein (HMGB1) have been reported in patients with calcific aortic valve disease (CAVD). However, the role of IL-18 and HMGB1 in the modulation of the valvular interstitial cell (VIC) phenotype remains unclear. We hypothesized that HMGB1 mediates IL-18-induced myofibroblastic transition of VICs. Methods: The expression of IL-18, HMGB1 and α-smooth muscle actin (α-SMA) in human aortic valves was evaluated by immunohistochemical staining, real-time polymerase chain reaction and immunoblotting. Plasma concentrations of IL-18 and HMGB1 were measured using the ELISA kit. Cultured human aortic VICs were used as an in vitro model. Results: Immunohistochemistry and immunoblotting revealed increased levels of IL-18, HMGB1 and α-SMA in calcific valves. Circulating IL-18 and HMGB1 levels were also higher in CAVD patients. In vitro, IL-18 induced upregulation of HMGB1 and α-SMA in VICs. Moreover, IL-18 induced secretion of HMGB1 to the extracellular space and activation of nuclear factor kappa-B (NF-κB). Blockade of NF-κB abrogated the upregulation and release of HMGB1 induced by IL-18. Whereas HMGB1 inhibition attenuated the IL-18-induced expression of α-SMA, HMGB1 enhanced the effect of IL-18. Conclusions: We demonstrated for the first time that both tissue and plasma levels of IL-18 and HMGB1 were increased in patients with CAVD. Mechanically, HMGB1 mediated IL-18-induced VIC myofibroblastic transition.

The Impact of Interleukin-18 and High-Mobility Group Box 1 Protein Signaling in Aortic Valve Calcification

“…A previous study has also demonstrated that nonrheumatic, calcified human aortic valves are characterized by increased IL-18 expression on immunohistochemistry [13]. The study of Wang et al [8] is important since it extends the current literature [13] and provides further support to the notion of IL-18 as a pivotal player in the pathogenesis of calcific aortic valve stenosis. …”

“…In this issue of Cardiology , Wang et al [8] provide some interesting findings on the potential role of interleukin-18 (IL-18) and high-mobility group box 1 protein (HMGB1) in valvular calcification. They demonstrate that human calcific aortic valves express higher levels of IL-18/HMGB1 than noncalcified aortic valves [8].…”

“…They demonstrate that human calcific aortic valves express higher levels of IL-18/HMGB1 than noncalcified aortic valves [8]. These data are supplemented by cell culture experiments demonstrating that HMGB1 is involved in IL-18-induced nuclear factor kappa B activation and the myofibroblastic transition of VICs.…”

“…In their study, Wang et al [8] demonstrate that both IL-18 circulating plasma levels as well as valve tissue protein levels of IL-18 are increased in patients with calcific aortic valve disease. A previous study has also demonstrated that nonrheumatic, calcified human aortic valves are characterized by increased IL-18 expression on immunohistochemistry [13].…”

“…Wang et al [8] suggest that the synergy of IL-18 with HMGB1 might be important for the development and/or progression of calcific aortic valve disease. Other studies have highlighted the importance of transforming growth factor β 1 signaling as well as the cross-talk of the Notch1-Wnt3a pathway for the osteoblastic differentiation of VICs and valve mineralization [3].…”