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Background: Calcific aortic valve disease is characterized by an abnormal mineralization of the aortic valve. Osteogenic activity in the aortic valve is under the control ofNOTCH1 , which regulates the expression of key pro-osteogenic genes such asRUNX2 andBMP2 . Long noncoding RNAs (lncRNAs) may reprogram cells by altering the gene expression pattern.Methods: Multidimensional genomic profiling was performed in human aortic valves to document the expression of lncRNAs and the DNA methylation pattern in calcific aortic valve disease. In-depth functional assays were carried out to document the impact of lncRNA on the mineralization of the aortic valve. Results: We documented that lncRNAH19 (H19 ) was increased in calcific aortic valve disease. Hypomethylation of the promoter region was observed in mineralized aortic valves and was inversely associated withH19 expression. Knockdown and overexpression experiments showed thatH19 induces a strong osteogenic phenotype by altering the NOTCH1 pathway. Gene promoter analyses showed thatH19 silencedNOTCH1 by preventing the recruitment of p53 to its promoter. A knockdown ofH19 in valve interstitial cells (VICs) increased the expression ofNOTCH1 and decreased the level ofRUNX2 andBMP2 , 2 downstream targets repressed byNOTCH1 . In rescue experiments, the transfection of a vector encoding for the active Notch intracellular domain preventedH19 -induced mineralization of valve interstitial cells.Conclusions: These findings indicate that a dysregulation of DNA methylation in the promoter ofH19 during calcific aortic valve disease is associated with a higher expression of this lncRNA, which promotes an osteogenic program by interfering with the expression ofNOTCH1.

Altered DNA Methylation of Long Noncoding RNA H19 in Calcific Aortic Valve Disease Promotes Mineralization by Silencing NOTCH1