Abstract 8608: Oxidized Low Density Lipoprotein Synergizes with Toll-Like Receptor 4 Agonist to Induce the Inflammatory and Osteogenic Responses in Human Aortic Valve Interstitial Cells
The inflammatory and osteogenic responses of aortic valve interstitial cells (AVICs) play an important role in the progression of calcific aortic valve stenosis. We found that stimulation of TLR4 induces the expression of inflammatory and osteogenic mediators in human HAVICs, indicating a role for TLR4 in the pathogenesis and progression of this cardiovascular disease. In patients with aortic valve stenosis, valvular tissue exhibits increased levels of oxidized LDL (oxLDL), and oxLDL induces the secretion of pro-inflammatory cytokines in monocytes and macrophages. However, it remains unclear whether oxLDL modulates the inflammatory and osteogenic responses in valvular cells. We tested the hypothesis that oxLDL augments the inflammatory and osteogenic responses to TLR4 stimulation in human AVICs. The purposes of this study were to determine: 1) whether oxLDL induces IL-6, ICAM-1 and BMP-2 in human AVICs, 2) whether oxLDL synergizes with TLR4 agonist endotoxin to augment the production of inflammatory and osteogenic mediators and 3) the mechanism by which oxLDL exerts an effect.
Methods and results: Human AVICs isolated from normal aortic valve were treated with TLR4 agonist endotoxin (0.1 μg/ml), oxLDL (20 µg/ml) or endotoxin plus oxLDL for 48 h. Endotoxin alone induced the production of IL-6, ICAM-1 and BMP-2 in human AVICs. OxLDL alone had no effect on IL-6 secretion and cellular ICAM-1 protein levels, while it induced a slight increase in cellular BMP-2 protein levels. Surprisingly, cells exposed to oxLDL and endotoxin produced markedly higher levels of IL-6 (3.4 folds), ICAM-1 (4.0 folds) and BMP-2 (3.5 folds) than cells expose to endotoxin alone. Similarly, oxLDL enhanced endotoxin-induced activation of Notch1. Inhibition of Notch1 reduced IL-6, ICAM-1, BMP-2 levels in cells treated with oxLDL and endotoxin. Further, Notch1 ligand Jagged1 also augments the inflammatory and osteogenic responses to endotoxin.
Conclusions: The Notch1 pathway augments TLR4-mediated inflammatory and osteogenic responses in human AVICs, and oxLDL synergizes with endotoxin to induce these responses through modulation of Notch1 activation. Thus, a synergy between oxLDL and TLR4 agonist may promote the progression of calcific aortic valve stenosis.
- © 2011 by American Heart Association, Inc.