Aortic Stenosis Hyalectan Remodeling Revealed by Proteomics and Glycoproteomics
Year: 2026
Type: article
Abstract: BACKGROUND: Calcific aortic valve (AV) disease (CAVD) is recognized as an active pathological process involving extracellular matrix remodeling. This study investigates extracellular matrix remodeling through proteomic analysis and a novel mouse model of aortic stenosis. METHODS: Proteomic and glycoproteomic analyses were conducted on AV leaflets from heart transplant donors (n=29) and patients with CAVD (n=17). Each CAVD sample was subdivided into noncalcified and calcified regions. To investigate the functional impact of extracellular matrix remodeling on aortic stenosis, we crossed apolipoprotein E-deficient mice ( ApoE −/− ) with mice lacking the catalytic domain of ADAMTS5 ( Adamts5 Δcat ) to generate a mouse model combining hyalectan accumulation with hypercholesterolemia. RESULTS: Proteomic and glycoproteomic analyses revealed hyalectan accumulation in CAVD compared with control valves. Versican predominated in noncalcified regions, while aggrecan was enriched in calcified regions. The shift in hyalectan composition correlated with changes in AV pressure gradient, elevated osteoblast-like cell markers, and inflammatory proteins, most notably pentraxin 3. Both versican and aggrecan are characterized by their ability to bind hyaluronan and serve as substrates of ADAMTS5. In Adamts5 Δcat /ApoE − /− mice, hyalectan accumulation was associated with narrowed aortic cusp separation and increased post-AV velocity. Proteomic analysis of AVs from Adamts5 Δcat /ApoE − /− mice revealed elevated versican, aggrecan, and pentraxin 3, recapitulating key features of human CAVD. Single-cell RNA sequencing and in vitro experiments linked versican to activated valve interstitial cells, while aggrecan colocalized with calcification markers in osteoblast-like cells. Pentraxin 3 was bound to hyaluronan and accumulated in calcified AVs. ADAMTS5 deficiency was sufficient to cause intact versican accumulation and promote valve interstitial cell activation, accompanied by increased expression of osteopontin. Osteopontin is a ligand of CD44, a principle hyaluronan receptor. CONCLUSIONS: This study highlights hyaluronan remodeling during aortic stenosis pathogenesis. A shift from versican to aggrecan in human CAVD correlates with changes in AV pressure gradient. In Adamts5 Δcat /ApoE − /− mice, impaired hyalectan catabolism promotes aortic stenosis.
Authors: Siqi Yin, Ursula Mayr, Javier Barallobre-Barreiro, Elisa Duregotti, Anna K. Barton, Rong Bing, Dyana Markose, Xiaoke Yin, Padmini Sarathchandra, Bhawana Singh, Wen-Yu Lin, Marika Fava, Lukas E. Schmidt, Ferheen Baig, Ajay M. Shah, Konstantinos Theofilatos, Najma Latif, Christian Hengstenberg, Tamás Radovits, Béla Merkely, Neil C. Henderson, Marc R. Dweck, Manuel Mayr
Institutions: Imperial College London, British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Centre for Inflammation Research, Tri-Service General Hospital, National Defense Medical Center, King's College London, British Heart Foundation, Medical University of Vienna, Semmelweis University
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7168564408