Figure - PMC

Skip to main content

An official website of the United States government

Here's how you know

Here's how you know

Official websites use .gov
A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS
A lock ( ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

View full-text article in PMC

. 2018 Mar 14;5:21. doi: 10.3389/fcvm.2018.00021

Search in PMC
Search in PubMed
View in NLM Catalog
Add to search

Copyright © 2018 Hulin, Hego, Lancellotti and Oury

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

PMC Copyright notice

CAVD is a multi-step disease. Upon valve endothelium damage, low-density-lipoprotein (LDL) and lipoprotein a [Lp(a)] accumulate. Oxidation of LDL (oxLDL) trigger infiltration of macrophages and T cells that express pro-inflammatory cytokines among which IL-6 and TNF-α. Proinflammatory cytokines impairs protective role of valve endothelial by inhibition of endothelial nitric oxide synthase (eNOS) and production of nitric oxide (NO). Therefore, oxidative stress (ROS) increases and contributes to enhance oxLDL. Concomitantly, valve interstitial cells (VICs) get activated by cytokines and oxLDL directly, or indirectly through autotaxin (ENPP2) and lysophosphatidyl acid (LPA). Therefore, VICs enter an osteogenic differentiation leading to calcific deposit and nodule formation. Activated VICs secrete glycosaminoglycans (GAGs), favoring further accumulation of oxLDL. Increased cyclooxygenase 2 (COX2) and its product prostaglandin (PTG), Wnt and BMP signaling have been shown to drive osteogenic differentiation while inhibition of IGF-1 signaling by dipeptidyl peptidase-4 (DPP4) contributes as well to pathogenesis. Also, Notch signaling, induced by NO, repress osteogenic differentiation. Finally, T cells favor osteogenesis and osteoclast formation by production of TNFSF11 but secrete Interferon-γ (IFN-γ) which limits calcium resorption. Altogether, aortic valve leaflets gets remodeled and stiffen leading to aortic valve stenosis. ROS: Reactive Oxygen Species. LPAR1: Lysosphosphatidyl Acid Receptor 1. TLR: Toll-like receptor. IL6: interleukin 6. TNF-α: Tumor necrosis factor- α. BMP: Bone Morphogenetic Protein. Morphogen. BMPR1: BMP Receptor 1. Fzd: Frizzled. RANK: Receptor Activator of Nuclear Factor kB. TNFSF11: RANK ligand.