Mol Med. 2026 May 8. doi: 10.1186/s10020-026-01499-0. Online ahead of print.
ABSTRACT
BACKGROUND: Aortic stenosis is a progressive fibro-inflammatory valvular disorder with major clinical burden and no disease-modifying pharmacological therapy. Defining molecular circuits associated with thrombo-inflammatory activation to extracellular matrix remodeling may enable future therapeutic targeting and biomarker development.
METHODS: Human aortic valves explanted from patients with severe aortic stenosis and non-stenotic surgical controls (aortic regurgitation) were profiled using a multi-layer mass spectrometry strategy. Global protein changes were quantified by label-free proteomics (data-independent acquisition). Extracellular matrix proteolysis was interrogated using an extracellular matrix-focused semi-tryptic peptide workflow. Collagen qualitative remodeling was assessed by mapping hydroxyproline enrichment. Differential abundance was evaluated using multiple-testing correction (false discovery rate). Selected candidates were validated by targeted multiple reaction monitoring, and elastin integrity was assessed histologically.
RESULTS: We identified 594 significantly modulated proteins in severe aortic stenosis, with predominant upregulation of complement/coagulation and extracellular matrix-related pathways. Targeted Multiple Reaction Monitoring confirmed key thrombo-inflammatory and matrix-associated candidates. Semi-tryptic profiling revealed a focused extracellular matrix degradomic signature dominated by small leucine-rich proteoglycans (decorin, lumican, PRELP), fibrillin-1, and collagen VI, consistent with preferential proteolytic targeting of structural matrix scaffolds. Histology showed marked elastin fragmentation in stenotic leaflets. Collagen post-translational modification analysis revealed increased hydroxyproline- bearing peptides across selected collagen chains despite minimal changes in total collagen abundance, indicating qualitative remodeling beyond protein accumulation.
CONCLUSIONS: An integrated proteomic-degradomic-post-translational modification framework reveals concomitant thrombo-inflammatory activation to matrix breakdown and qualitative collagen remodeling in severe aortic stenosis, highlighting molecular circuits that may inform future biomarker development and therapeutic target discovery.
PMID:42104263 | DOI:10.1186/s10020-026-01499-0