Wnt5a-mediated Adipo-Cardiac Interorgan Communication in HFpEF

Area of Science:

• Cardiovascular Biology
• Metabolic Disease Research
• Molecular Mechanisms of Heart Failure

Background:

• Obesity is a significant risk factor for heart failure with preserved ejection fraction (HFpEF).
• The exact mechanisms linking obesity to cardiac remodeling in HFpEF remain unclear.
• Previous research suggests increased natriuretic peptide clearance receptor (Nprc) expression may contribute to cardiac remodeling in response to high-fat diets.

Purpose of the Study:

• To investigate the role of Nprc in the development and reversal of experimental HFpEF.
• To test the hypothesis that Nprc is central to preventing and reversing HFpEF.
• To elucidate the specific cellular mechanisms involving Nprc in obesity-associated cardiac dysfunction.

Main Methods:

• Generated Nprc knockout mice with global, cardiomyocyte-specific, or adipocyte-specific gene disruption.
• Induced HFpEF using a two-hit model (L-NAME and high-fat diet).
• Assessed outcomes via echocardiography, exercise testing, catheterization, and histology; utilized bulk RNA sequencing for gene expression analysis in adipose tissue.

Main Results:

• Global inducible Nprc knockout ameliorated HFpEF features, including structural, hemodynamic, and exercise tolerance deficits.
• The beneficial effects were attributed to adipocyte-specific Nprc disruption, not cardiomyocyte-specific.
• Adipocyte Nprc knockout led to downregulation of Wnt pathways, notably Wnt5a; Wnt5a administration increased cardiomyocyte hypertrophy, while blocking Wnt ligand release improved cardiac remodeling in HFpEF.

Conclusions:

• Identified a novel crosstalk between adipocytes and cardiomyocytes in obesity-associated HFpEF.
• Demonstrated that natriuretic peptide-mediated inhibition of Wnt5a release from adipocytes drives cardiac remodeling.
• Nprc plays a critical role in adipocyte-cardiac crosstalk, offering a potential therapeutic target for obesity-related HFpEF.