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Regulation of Aortic Valve EndMT and Calcific Susceptibility via Canonical NFkB Signaling
Terence Gee1, Emily Farrar1, Kevin Hsu1, Bin Zhou2, Jonathan Butcher1.
1Cornell University, Ithaca, NY, USA, 2Einstein College of Medicine, New York, NY, USA.

OBJECTIVE: The aim of this study was to further understand the role of inflammation, a feature in aortic valve (AV) pathology, in driving tissue degenerative processes. Canonical NFkB signaling governs inflammatory and osteogenic pathways/processes, and may therefore act as a major regulator in calcific aortic valve disease initiation/progression.
METHODS: We created a mouse model of aortic valve degeneration with local NFkB inactivation, using LDL-receptor knock-out with a valve-specific deletion of IKKB. LDLr null and multi-transgenic mice were fed a high fat diet for 5 months and analyzed via echocardiography and immunohistochemistry. 3D in vitro cultures using porcine aortic valve interstitial cells were used for mechanistic studies of EMT and calcification pathways, subjected to both transfection and small molecule gain and loss of function assays.
RESULTS: The pro-AV disease LDLr-/- condition was characterized by increased leaflet thickness and AV peak ejection velocity, which were restored to control levels with IKKBfl/fl conditional deletion. NFkB p65 expression and nuclear localization were elevated within VEC of the AVD model. Nuclear localization and downstream inflammatory activation was abrogated via the IKKBfl/fl, confirmed via VCAM-1 staining. In LDLr-/- mice, we observed postnatal EndMT via co-expression of endothelial (CD31) and mesenchymal (aSMA) proteins, which again was abrogated in the LDLr-/-IKKBfl/fl. 3D porcine AV cell culture with p65-specific overexpression and inhibition show that NFkB p65 regulates EndMT and calcification of both endothelial and interstitial cell populations, which were both inhibited by deactivation of NFkB.
CONCLUSIONS: Our results provides further evidence of NFkB-driven postnatal EndMT in the aortic valve, denoting an active role of the endothelium in the degenerative process. The demonstrated connection between reduced inflammatory activation and improved valvular function affirms the positive effects of intervention/mitigation of inflammation in AVD management.


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