Lnc-ing NOTCH1 to Idiopathic Calcific Aortic Valve Disease
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Article, see p 1848
Calcific aortic valve disease (CAVD) is an age-related disorder that causes significant cardiovascular morbidity and mortality and is directly responsible for ≈15 000 patient deaths per year in the United States. Currently, the molecular mechanism by which CAVD initiates is unknown, making discovery of a nonsurgical strategy challenging.1 Garg et al2 made a seminal discovery in 2005 when they showed NOTCH1 mutations led to heritable CAVD. Since then, the heart valve research community has sought a causal mechanism that could connect NOTCH1 dysfunction to idiopathic CAVD. That causal link has been elusive until the recent and impressive work by Hadji et al3 in this issue of Circulation demonstrated that the promoter region of the long noncoding (lnc) RNA H19 is hypomethylated in patients with CAVD. This hypomethylation, in turn, increases H19 expression in the valve interstitial cells (VICs), where it prevents NOTCH1 transcription by seemingly blocking or outcompeting p53’s recruitment to the NOTCH1 promoter. Thus, H19 appears to be the missing link (or lncRNA, if you will) connecting NOTCH1 to idiopathic CAVD.
LncRNAs are transcripts that lack protein translation potential, but they are master regulators of gene expression and their own expression dysregulation is associated with a variety of human pathologies. H19 controls gene expression at multiple levels, from chromatin modification to direct protein inhibition, and has been labeled as the multitasking lncRNA prototype.4 H19 …