Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Cell Adhesion Molecules

Background:

• Wnt signaling reactivation drives cardiac remodeling and fibrosis under pathological stress.
• The cell surface receptor Cdon (cell-adhesion associated, oncogene regulated) is known to suppress Wnt signaling in neuronal differentiation.
• The role of Cdon in cardiac function and disease remains unexplored.

Purpose of the Study:

• To investigate the role of Cdon in cardiac function, remodeling, and fibrosis.
• To elucidate the molecular mechanisms by which Cdon influences cardiac pathology.
• To assess the therapeutic potential of targeting Cdon in cardiac disease.

Main Methods:

• Analysis of Cdon expression and localization in mouse and human hearts.
• Phenotypic characterization of Cdon-deficient mice, including cardiac function and electrophysiology assessments.
• Molecular analyses of fibrosis, gene expression (including Wnt pathway and Connexin 43), and intercellular coupling in Cdon-deficient hearts and cardiomyocytes.
• In vitro studies using cardiomyocytes treated with Wnt activators or inhibitors.

Main Results:

• Cdon is expressed at the intercalated disk in cardiac tissue.
• Cdon deficiency results in cardiac dysfunction, reduced ejection fraction, ECG abnormalities, increased cardiac fibrosis, and upregulation of remodeling genes.
• Cdon deficiency leads to electrical remodeling, characterized by altered Connexin 43 (Cx43) expression and aberrant gap junction activity.
• Cdon deficiency causes hyperactive Wnt signaling, evidenced by increased β-catenin and Axin2.
• Wnt pathway activation reduces Cdon levels, suggesting a negative feedback loop.
• Inhibition of Wnt signaling ameliorates Cdon depletion-induced fibrosis and Cx43 upregulation.

Conclusions:

• Cdon deficiency promotes Wnt/β-catenin signaling hyperactivity, leading to aberrant intercellular coupling and cardiac fibrosis.
• Cdon plays a critical protective role against pathological cardiac remodeling and fibrosis.
• Cdon represents a promising therapeutic target for treating cardiac fibrosis and cardiomyopathy.