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Published on: April 21, 2010
Wnt Signaling Inhibition Prevents Postnatal Inflammation and Disease Progression in Mouse Congenital Myxomatous Valve
Na Xu1,2, Christina M Alfieri1, Yang Yu3
1Division of Molecular Cardiovascular Biology, the Heart Institute (N.X., C.M.A., K.E.Y.), Cincinnati Children's Hospital Medical Center, OH.
Background:
Myxomatous valve disease (MVD) is the most common cause of mitral regurgitation, leading to impaired cardiac function and heart failure. MVD in a mouse model of Marfan syndrome includes valve leaflet thickening and progressive valve degeneration. However, the underlying mechanisms by which the disease progresses remain undefined.
Methods:
Mice with Fibrillin 1 gene variant Fbn1C1039G/+ recapitulate histopathologic features of Marfan syndrome, and Wnt (Wingless-related integration site) signaling activity was detected in TCF/Lef-lacZ (T-cell factor/lymphoid enhancer factor-β-galactosidase) reporter mice. Single-cell RNA sequencing was performed from mitral valves of wild-type and Fbn1C1039G/+ mice at 1 month of age. Inhibition of Wnt signaling was achieved by conditional induction of the secreted Wnt inhibitor Dkk1 (Dickkopf-1) expression in periostin-expressing valve interstitial cells of Periostin-Cre; tetO-Dkk1; R26rtTA; TCF/Lef-lacZ; Fbn1C1039G/+ mice. Dietary doxycycline was administered for 1 month beginning with MVD initiation (1-month-old) or MVD progression (2-month-old). Histological evaluation and immunofluorescence for ECM (extracellular matrix) and immune cells were performed.
Results:
Wnt signaling is activated early in mitral valve disease progression, before immune cell infiltration in Fbn1C1039G/+ mice. Single-cell transcriptomics revealed similar mitral valve cell heterogeneity between wild-type and Fbn1C1039G/+ mice at 1 month of age. Wnt pathway genes were predominantly expressed in valve interstitial cells and valve endothelial cells of Fbn1C1039G/+ mice. Inhibition of Wnt signaling in Fbn1C1039G/+ mice at 1 month of age prevented the initiation of MVD as indicated by improved ECM remodeling and reduced valve leaflet thickness with decreased infiltrating macrophages. However, later, Wnt inhibition starting at 2 months did not prevent the progression of MVD.
Conclusions:
Wnt signaling is involved in the initiation of mitral valve abnormalities and inflammation but is not responsible for later-stage valve disease progression once it has been initiated. Thus, Wnt signaling contributes to MVD progression in a time-dependent manner and provides a promising therapeutic target for the early treatment of congenital MVD in Marfan syndrome.
Insights
Wnt signaling initiates mitral valve disease in Marfan syndrome by causing valve thickening and inflammation. Early intervention targeting Wnt signaling can prevent disease onset, but is ineffective once the condition progresses.
Area of Science:
- Cardiovascular Biology
- Genetics
- Molecular Biology
Background:
- Myxomatous valve disease (MVD) is a leading cause of mitral regurgitation and heart failure.
- MVD in Marfan syndrome mouse models involves valve thickening and degeneration, with unclear mechanisms.
- Understanding MVD progression is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of Wnt signaling in the initiation and progression of MVD in a Marfan syndrome mouse model.
- To determine if inhibiting Wnt signaling can prevent or reverse MVD.
- To identify potential therapeutic targets for early MVD intervention.
Main Methods:
- Utilized Fibrillin 1 (Fbn1) mutant mice and TCF/Lef-lacZ reporter mice to study Wnt signaling.
- Performed single-cell RNA sequencing on mitral valves from wild-type and Fbn1 mutant mice.
- Inhibited Wnt signaling using Dkk1 in a conditional knockout model, administered at different disease stages.
Main Results:
- Wnt signaling activation precedes immune cell infiltration in MVD progression.
- Early Wnt inhibition (1 month) prevented MVD initiation, reducing valve thickening and macrophage infiltration.
- Late Wnt inhibition (2 months) did not prevent established MVD progression.
Conclusions:
- Wnt signaling is critical for MVD initiation and early inflammation but not for later disease progression.
- Wnt signaling's role in MVD is time-dependent, highlighting the importance of early therapeutic intervention.
- Targeting Wnt signaling early offers a promising strategy for congenital MVD in Marfan syndrome.
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