Abstract 16417: Role of Long Non-Coding RNAs in the Regulation of the Notch Pathway: Implication for Calcific Aortic Valve Stenosis
Introduction: Calcific aortic valve stenosis (CAVS) is the most common valvular heart disease. The disease process is largely driven by an abnormal mineralization of leaflets. The Notch pathway is involved in the osteogenic transition of valve interstitial cells (VICs) and palys an important role in CAVS. However, the molecular processes involved in the regulation of Notch signaling in CAVS remain to be determined
Hypothesis: Long non-coding RNAs (Long ncRNAs) may be involved in the control of the Notch pathway
Methods: We analyzed the gene expression pattern of valvular tissues (controls and CAVS) using microarrays. Furthermore, we explored the role of a Long ncRNA on the mineralization of VICs. Signaling of the Notch pathway was investigated by promoter luciferase activity and by analyzing mRNA levels of target genes
Results: A transcriptomic study revealed that a Long ncRNA is overexpressed in CAVS. This result was confirmed by q-PCR in a larger group of aortic valve tissues (n=152). Silencing and overexpression with a vector encoding this Long ncRNA decreased and increased the moneralization of VICs, respectively. Overexpression of this Long ncRNA led to lower activity of the Notch1 promoter, which resulted in a substantial decrease in the cleaved intracellular portion of Notch1 receptor (NICD). The transfection of the Long ncRNA in VICs decreased significantly the activity of the RBP-jk response element located downstream of NICD and resulted in the overexpression of BMP2 and Runx2, two target genes repressed by the hairy-related family genes, which are activated by the complex formed of NICD and RBP-jk. In a rescue experiment in VICs, the transfection of a vector encoding NICD prevented the mineralization induced by the Long ncRNA
Conclusions: Overexpression of a Long ncRNA in CAVS promoted the dysfunction of the Notch signaling pathway and induced the osteoblastic transition of VICs. To our knowledge, this is the first study to report that a Long ncRNA plays a crucial role in Notch signaling and the development of CAVS
Author Disclosures: F. Hadji: None. M. Boulanger: None. S. Guauque-Olarte: None. R. Bouchareb: None. Y. Bossé: None. P. Mathieu: None.
- © 2014 by American Heart Association, Inc.