Abstract 13589: A Novel Role of Intercellular Adhesion Molecule-1 Signaling via Notch1 in Mediating Bone Morphogenetic Protein-2 Expression in Human Aortic Valve Interstitial Cells
Calcific aortic valve stenosis is a chronic inflammatory disease. Aortic valve interstitial cells (AVICs) play an important role in the valvular inflammatory and osteogenic responses. We observed that pro-inflammatory stimuli induce the expression of intercellular adhesion molecule-1 (ICAM-1) and bone morphogenetic protein-2 (BMP-2) in human AVICs. However, the mechanism underlying the interaction between the pro-inflammatory and pro-osteogenic pathways remains incompletely understood. While ICAM-1 possesses signaling function, it is unknown whether ICAM-1 signaling modulates BMP-2 expression. This study tested the
hypothesis that ICAM-1 has a novel role in mediating BMP-2 expression in human AVICs.
Methods and results: Human AVICs were isolated from normal aortic valve leaflets and cultured in M199 medium. Pre-stimulation of human AVICs with a low level of lipopolysacharride (LPS, 0.05 µg/ml) increased total and cell surface levels of ICAM-1. Ligation of ICAM-1 with leukocyte function-associated factor-1 (LFA-1) after LPS stimulation markedly increased cellular BMP-2 levels. Similarly, ligation of ICAM-1 by antibody cross-linking up-regulated BMP-2 expression in human AVICs. In investigation of the ICAM-1 signaling pathway that is responsible for up-regulation of BMP-2 expression, we found that LFA-1 promoted Notch1 cleavage and NF-κB p65 phosphorylation in cells with or without LPS pre-treatment. Inhibition of NF-κB with SN50 markedly reduced LFA-1-induced BMP-2 expression in cells pre-treated with LPS. Surprisingly, inhibition of Notch1 cleavage with γ-secretase inhibitor DAPT essentially abrogated LFA-1-induced NF-κB phosphorylation and BMP-2 expression.
Conclusions: Ligation of ICAM-1 by leukocyte β-integrin LFA-1 activates the Notch1 pathway. Notch1 up-regulates BMP-2 expression in human AVICs through activation of NF-κB. The results of this study demonstrate a novel role of ICAM-1 in translation of pro-inflammatory signal into osteogenic response in human AVICs and suggest that ICAM-1 expressed on the surfaces of AVICs not only could mediate valvular tissue inflammation, but also may contribute to the mechanism of aortic valve calcification by up-regulation of BMP-2 expression.
- © 2012 by American Heart Association, Inc.