PXD078502-1

PXD078502 is an original dataset announced via ProteomeXchange.

Title	Hyalectan Remodeling Contributes to Aortic Stenosis: Insights from Proteomics and Glycoproteomics
Description	BACKGROUND: Calcific aortic valve disease (CAVD) is increasingly recognized as an active pathological process involving extracellular matrix (ECM) remodeling. This study investigates ECM remodeling through proteomic analysis and a novel mouse model of aortic stenosis (AS). METHODS: Proteomic and glycoproteomic analyses were conducted on aortic valve (AV) leaflets from heart transplant donors (n=29) and CAVD patients (n=17). Each CAVD sample was subdivided into non-calcified and calcified regions. To investigate the functional impact of ECM remodeling on AS, we crossed apolipoprotein E-deficient mice (ApoE-/-) with mice lacking the catalytic domain of ADAMTS5 (Adamts5Δcat) to generate a mouse model combining hyalectan accumulation with hypercholesterolemia. RESULTS: Proteomic and glycoproteomic analyses revealed hyalectan accumulation in CAVD compared to control valves. Versican predominated in non-calcified regions, while aggrecan was enriched in calcified regions. The shift in hyalectan composition correlated to 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 major substrates of ADAMTS5. In Adamts5Δcat/ApoE-/- mice, hyalectan accumulation was associated with a significant narrowed aortic cusps separation, and increased post AV velocity. Proteomic analysis of AVs from Adamts5Δcat/ApoE-/- mice revealed elevated versican, aggrecan, and pentraxin 3, recapitulating key features of human CAVD. Single-cell RNA sequencing and in vitro experiment linked versican to activated valve interstitial cells, while aggrecan co-localized 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 differentiation, as evidenced by increased expression of osteopontin, which binds to hyaluronan receptors. CONCLUSIONS: This study highlights hyalectan remodelling during AS pathogenesis. A shift from versican to aggrecan in human CAVD correlates to changes in AV pressure gradient. In Adamts5Δcat/ApoE-/- mice, impaired hyalectan catabolism promotes AS.
HostingRepository	PRIDE
AnnounceDate	2026-07-16
AnnouncementXML	Submission_2026-07-16_05:18:52.552.xml
DigitalObjectIdentifier	https://doi.org/10.6019/PXD078502
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	XIAOKE YIN
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	monohydroxylated residue; 1x(18)O labeled deamidated L-asparagine; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2026-05-18 09:45:28	ID requested
⏵ 1	2026-07-16 05:18:53	announced

10.6019/PXD078502;

10.1161/ATVBAHA.126.323867;

submitter keyword: ADAMTS, Proteoglycan,Calcific aortic valve disease, Aortic stenosis, Extracellular matrix

Manuel Mayr
contact affiliation	National Heart and Lung Institute, Imperial College London, London, UK
contact email	m.mayr@imperial.ac.uk
lab head
XIAOKE YIN
contact affiliation	National Heart and Lung Institute, Faculty of Medicine, Imperial College London
contact email	xiaoke.yin@imperial.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD078502
     1. Label: PRIDE project
     2. Name: Hyalectan Remodeling Contributes to Aortic Stenosis: Insights from Proteomics and Glycoproteomics