Cardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Fibrosis Research

Background:

• Tissue fibrosis and organ dysfunction are key features of age-related diseases like heart failure.
• A common underlying pathway for these conditions remains largely unknown.
• Cardiac fibroblasts and cardiomyocytes play crucial roles in cardiac health and disease progression.

Purpose of the Study:

• To investigate the role of high-temperature requirement A serine peptidase 3 (Htra3) in cardiac fibrosis and heart failure.
• To elucidate the molecular mechanisms linking cardiac fibroblasts and cardiomyocytes in heart disease.
• To identify potential therapeutic targets for heart failure.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq)
• Spatial transcriptomics
• Genetic perturbation studies
• Analysis of human plasma proteome and cardiomyocyte transcriptome

Main Results:

• Htra3 degrades transforming growth factor-β (TGF-β), preserving quiescent cardiac fibroblast identity.
• Pressure overload downregulates Htra3, activating TGF-β signaling, leading to cardiac fibrosis and cardiomyocyte dysfunction.
• Htra3 overexpression ameliorates cardiac dysfunction and fibrosis post-pressure overload.
• IGFBP7, a TGF-β downstream cytokine, is a predictable marker for advanced heart failure in humans.

Conclusions:

• The Htra3-TGF-β-IGFBP7 pathway is critical for regulating cardiac fibroblast function and cardiomyocyte homeostasis.
• Htra3 plays a protective role against cardiac fibrosis and heart failure.
• This pathway represents a potential therapeutic target for treating heart failure.