Myxomatous Mitral Valve Degeneration Associated with Elastin Accumulation in LTBP2-Deficient Mice

ABSTRACT: Background: Mitral valve prolapse (MVP) is a common valvular heart disease associated related to substantial morbidity and potential mortality. The molecular mechanisms underlying disease development remain incompletely understood. We previously identified a large family in which a missense variant in LTBP2 (Val1506Met) co-segregated with MVP, suggesting a role for LTBP2 in maintaining mitral valve integrity. Objective: To investigate the role of LTBP2 in mitral valve extracellular matrix (ECM) homeostasis and its contribution to MVP pathogenesis. Methods: LTBP2 knockout (KO) mice and primary fibroblast cultures were used to assess the effects of LTBP2 deficiency on ECM organization. Immunofluorescence staining was performed on mitral valve tissue and cultured fibroblasts to evaluate ECM protein expression and localization. Scanning electron microscopy (SEM) was used to examine microfibrillar ECM architecture, while quantitative RT-PCR and RNA sequencing were employed to assess ECM-related gene expression and pathway alterations. Results: LTBP2 deficiency resulted in significant alterations in ECM organization. Immunofluorescence analysis demonstrated increased elastin expression in KO mitral valves and fibroblasts, whereas fibrillin-1, collagen III, and fibulin-5 levels were mostly unchanged. SEM revealed significant disorganization of the microfibrillar ECM architecture in LTBP2-deficient mitral valves. Consistent with these findings, qRT-PCR confirmed significantly increased elastin expression in KO fibroblasts. RNA-seq pathway analysis identified significant enrichment of pathways related to extracellular matrix organization, elastic fiber formation, and TGF-β signaling. Conclusions: These findings demonstrate that LTBP2 is a critical regulator of mitral valve ECM homeostasis. Loss of LTBP2 leads to elastin accumulation, disruption of ECM architecture, and dysregulation of ECM-related signaling pathways, providing mechanistic insight into how LTBP2 dysfunction may contribute to myxomatous degeneration and MVP pathogenesis

ORGANISM(S): Mus musculus

PROVIDER: GSE344076 | GEO | 2026/08/26

REPOSITORIES: GEO