Wnt5a is elevated in heart failure and affects cardiac fibroblast function.

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Cell Signaling

Background:

• Wnt signaling pathway dysregulation is implicated in heart failure (HF).
• Wnt5a inhibition shows promise in preclinical HF models.
• The specific role of Wnt5a in human HF and cardiac cells requires elucidation.

Purpose of the Study:

• To investigate Wnt5a regulation in human HF patients.
• To determine the effects of Wnt5a on primary cardiac fibroblasts.
• To elucidate the signaling mechanisms underlying Wnt5a actions in the heart.

Main Methods:

• Quantification of serum and myocardial Wnt5a levels in HF patients.
• Analysis of Wnt5a, IL-6, and TIMP-1 mRNA and protein expression.
• In vitro studies using primary mouse and human cardiac fibroblasts treated with recombinant Wnt5a.
• Assessment of β-catenin and ERK1/2 signaling pathways.

Main Results:

• Serum Wnt5a levels were elevated in HF patients and correlated with disease severity.
• Myocardial Wnt5a mRNA and protein were upregulated in HF and decreased after LVAD therapy.
• Wnt5a induced IL-6 and TIMP-1 release in cardiac fibroblasts via ERK1/2 activation.
• Wnt5a did not impact β-catenin levels.

Conclusions:

• Wnt5a is upregulated in human HF and associated with progressive disease.
• Wnt5a promotes IL-6 and TIMP-1 release in cardiac fibroblasts, suggesting a role in myocardial inflammation and fibrosis.
• Targeting Wnt5a or its downstream signaling may offer therapeutic strategies for HF.