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NFkB activation drives mesenchymal transformation and susceptibility to calcification in aortic valve endothelial cells
Author(s) -
Farrar Emily Jean,
Butcher Jonathan T
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.386.10
Subject(s) - mesenchymal stem cell , calcification , aortic valve , microbiology and biotechnology , chemistry , medicine , cardiology , biology
Treatment of calcific aortic valve disease (CAVD) remains difficult due to limited understanding of the initial pathological activators. The early inflammation stage is known to stimulate an endothelial to mesenchymal transition (EndMT) of valve endothelial cells (VEC), but the role of the transformed cells in later disease is unknown. Characterization of EndMT VEC revealed high expression of NFκB, α‐SMA, Snai1, MMP‐9, and extracellular matrix remodeling capabilities. Transfection of VEC with NFκB over‐expression and inhibition plasmids showed that NFκB is sufficient and necessary to induce EndMT. Further, when cultured in an osteogenic environment, VEC+NFκB had increased α‐SMA (50.4+/− 3.1 fold), osteocalcin (16.1+/−1.8 fold) runx‐2 (14.7+/−.8 fold), and calcium deposition compared to controls. In diseased human valves, cells with activated NFkB localized near calcific nodules and co‐expressed CD31 and α‐SMA, suggesting EndMT origin. Together, these results suggest that transformed VEC are key players in aortic valve calcification and NFκB‐inhibition is an attractive valve specific intervention strategy in the early stages of CAVD. Funding: NIH 1R01HL110328–01