Abstract 8592: Cross-Talk Between the Toll-Like Receptor 4 and Notch1 Pathways Augments the Inflammatory Response to Endotoxin in the Interstitial Cells of Stenotic Human Aortic Valves
Due to limited knowledge of the mechanisms of aortic valve stenosis, pharmacological intervention of this cardiovascular disease remains unavailable. Aortic valve stenosis is a chronic inflammatory disease, and aortic valve interstitial cells (AVICs) play an important role in the valvular inflammatory response. Oral bacteria have been found in stenotic aortic valve leaflets, and we recently found that stimulation of TLR4 in human AVICs induces the expression of ICAM-1 and BMP-2. While AVICs from stenotic aortic valves has an enhanced response to the TLR4 agonist endotoxin, the mechanism underlying the enhanced response is unknown. Activated Notch1 is found to modulate NF-κB activity in human leukemic T-cells, and endotoxin induces Notch1 activation in cultured macrophages. We tested the hypothesis that xcessive cross-talk between the TLR4 and Notch1 pathways augments the inflammatory response to endotoxin in diseased AVICs. The purposes of this study were to investigate: 1) whether TLR4 stimulation results in enhanced Notch1 activation in diseased AVICs, 2) whether inhibition of Notch1 attenuates the inflammatory response to TLR4 stimulation in diseased cells and 3) whether activation of Notch1 augments the inflammatory response to TLR4 stimulation in healthy AVICs.
Methods and results: Human AVICs were isolated from normal and stenotic aortic valve leaflets. IL-6, MCP-1 and ICAM-1 were analyzed following treatment with endotoxin. Cells from diseased valves produced greater levels of cytokines and ICAM-1, and exhibited enhanced Jagged1 release and Notch1 activation after TLR4 stimulation. Inhibition of Notch1 greatly reduced the inflammatory response in diseased cells. Stimulation of Notch1 with Jagged1 or over-expression of Notch1 intracellular domain in healthy AVICs enhanced the production of cytokines and ICAM-1 induced by TLR4 stimulation.
Conclusion: Notch1 enhances the inflammatory response to TLR4 stimulation in human AVICs. Excessive crosstalk between the TLR4 and Notch1 pathways is responsible, at least in part, for the augmentation of the inflammatory response to TLR4 agonist in AVICs of stenotic aortic valves. The Notch1 and TLR4 pathways could be therapeutic targets for regulation of aortic valve inflammatory response.
- © 2011 by American Heart Association, Inc.