Lnc-ing NOTCH1 to Idiopathic Calcific Aortic Valve Disease
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 USA. Currently, the molecular mechanism by which CAVD initiates is unknown, making discovery of a non-surgical strategy challenging (reviewed in 1). Garg et al. made a seminal discovery in 2005 when they showed NOTCH1 mutations led to heritable CAVD.2 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 Hadjj et al., in this issue of Circulation, demonstrated that the promoter region of the long non-coding (lnc) RNA H19 is hypomethylated in patients with CAVD.3 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.
- Received October 11, 2016.
- Revision received October 14, 2016.
- Accepted October 20, 2016.