Dkk3 prevents familial dilated cardiomyopathy development through Wnt pathway

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Wnt Signaling Pathway

Background:

• The role of Dickkopf 3 (Dkk3) in familial dilated cardiomyopathy (FDCM) pathogenesis and its interaction with Wnt signaling in cardiac tissue are not well understood.
• Dkk3 expression is downregulated in adult wild-type mouse hearts but upregulated in models of dilated cardiomyopathy (DCM).

Purpose of the Study:

• To investigate the role of Dickkopf 3 (Dkk3) in the development of familial dilated cardiomyopathy (FDCM).
• To determine if and how Dkk3 influences Wnt signaling pathways within heart tissues.
• To evaluate Dkk3 as a potential therapeutic target for cardiomyopathy and heart failure.

Main Methods:

• Utilized Dkk3 transgenic and knockout mouse models, alongside cTnT(R141W) transgenic mice exhibiting DCM phenotypes.
• Assessed survival rates, cardiac morphology, and pathological changes in response to Dkk3 manipulation.
• Analyzed the expression of key proteins in both canonical (Dvl1, β-catenin, c-Myc, Axin2) and noncanonical (JNK, CAMKII, HDAC4) Wnt pathways.

Main Results:

• Transgenic Dkk3 expression improved survival and ameliorated cardiac dysfunction and pathology in cTnT(R141W) mice.
• Dkk3 knockout worsened survival and aggravated DCM phenotypes in cTnT(R141W) mice.
• Dkk3 upregulated canonical Wnt pathway proteins and downregulated noncanonical Wnt pathway proteins, with knockout reversing these effects.

Conclusions:

• Dickkopf 3 (Dkk3) demonstrates a protective effect against familial dilated cardiomyopathy (FDCM) development in mice, particularly during the compensatory stage.
• The protective mechanism involves the activation of the canonical Wnt pathway and inhibition of the noncanonical Wnt pathway.
• Dkk3 represents a promising therapeutic target for treating cardiomyopathy and heart failure.