These findings indicate that a dysregulation of DNA methylation in the promoter of H19 during calcific aortic valve disease is associated with a higher expression of this lncRNA, which promotes an osteogenic program by interfering with the expression of NOTCH1.
Finally, Notch1 and NOS3 (endothelial NO synthase) display an in vivo genetic interaction critical for proper valve morphogenesis and the development of aortic valve disease.
This finding was supported by the discovery of a NOTCH1 frameshift mutation in an unrelated family with similar aortic valve disease, suggesting that NOTCH1 haploinsufficiency was a genetic cause of aortic valve malformations and calcification.
These results suggest that NOTCH1 mutations cause an early developmental defect in the aortic valve and a later de-repression of calcium deposition that causes progressive aortic valve disease.