Scientists identified potential therapeutic targets for aortic stenosis

New insights into the molecular and cellular development of a rare heart defect.

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Supravalvular aortic stenosis (SVAS) is a rare congenital heart defect caused by mutations or deletion of the elastin gene and characterized by narrowing the aorta. Now, scientists from Yale University have offered insights into aortic stenosis’s molecular and cellular development.

Scientists mainly identified the role of the gene Notch3 in regulating vascular smooth muscle cell (SMC) proliferation. SMC proliferation is the leading cause of stenosis during elastin deficiency.

Scientists focused on the role of the NOTCH signaling pathway, specifically the ligand Jag1 and Notch3 receptor, in cardiovascular diseases associated with elastin deficiency.

This study enrolled mice models with elastin deficiency, human aortic SMCs, and SMCs derived from induced pluripotent stem cells of SVAS and WBS patients. They found that elastin deficiency in SMCs activates the Notch3 pathway signaling via epigenetic mechanisms. These mechanisms alter the physical structure of DNA to modulate gene activity.

Deficiency in elastin reduces levels of DNMT1, an enzyme known to methylate DNA. This reduction prompts gene activation, culminating in Notch3 pathway over-activation.

In mice lacking elastin, treatment with a pharmacological inhibitor of the Notch pathway known as DAPT, gene deletion of Notch3, or SMC-specific deletion of Jag1 restoratively affects the aortic wall.

Scientists are planning to dig deeper to understand better elastin-mediated regulation of the SMC epigenome in vascular development and pathogenesis of other cardiovascular diseases linked with elastin damage.

Journal Reference:

  1. Jui M Dave et al. JAGGED1/NOTCH3 activation promotes aortic hypermuscularization and stenosis in elastin deficiency. Journal of Clinical Investigation, 2022; DOI: 10.1172/JCI142338