Year-end Sale % OFF 
Abstract
Background: Our current concept of aortic valve stenosis (AS) development suggests that local chronic inflammation drives fibrosis and calcification of the valve cusps. This remodeling is driven by endothelial to mesenchymal transition (EndMT) of valvular endothelial cells (VECs) and by calcification of valvular interstitial cells (VICs). In a preliminary screening, we found Toll-like receptor 3 (TLR3) expression increased in human AS samples. Therefore, aim of this study was to investigate the role of TLR3 in the pathogenesis of AS. Methods/Results: We confirmed TLR3 expression in cultured human VICs and VECs. Upon specific TLR3 stimulation with PolyI:C, both VICs and VECs displayed a positive feedback with increased TLR3 expression. Concomitant treatment of PolyI:C-stimulated VICs and VECs with the TLR3/RNA complex inhibitor (C4a) significantly blunted this response. Importantly, the TLR3-mediated pro-inflammatory and calcifying response of VICs and EndMT by VECs was significantly reduced by TLR3-inhibtion with C4a.To examine the role or TLR3 in AS development, a wire injury induced AS mouse model was used. Valves were explanted and stained with hematoxylin/eosin, Sirius red, von Kossa, or anti CD68. PolyI:C treatment promoted AS, as demonstrated by increased valve cusp thickness and pronounced valvular inflammation. Interestingly, AS development was nearly absent in TLR3 deficient mice suggesting a critical role of endogenous TLR3 ligands in this model. Treatment of mice with C4a after wire-injury of the aortic valve significantly reduced both morphological and functional parameters of AS development. Conclusion: These findings not only support the role of endogenous TLR3 activation in the development of AS but suggest that specific TLR3 inhibition might be beneficial for the treatment or prevention of AS. Further studies are required to decipher the exact mechanisms how TLR3 contributes to AS.
Published Version
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.
