Heart failure-specific cardiac fibroblasts contribute to cardiac dysfunction via the MYC-CXCL1-CXCR2 axis

Area of Science:

• Cardiology
• Molecular Biology
• Cell Biology

Background:

• Heart failure (HF) is a significant global health concern.
• Research predominantly focuses on cardiomyocytes, overlooking the role of cardiac fibroblasts (CFs).
• Identifying novel cellular mechanisms in HF is crucial for therapeutic development.

Purpose of the Study:

• To investigate the role of cardiac fibroblasts (CFs) in the pathogenesis of heart failure (HF).
• To identify specific CF subpopulations and molecular pathways involved in HF.
• To explore the MYC-CXCL1-CXCR2 axis as a potential therapeutic target for HF.

Main Methods:

• Single-cell RNA sequencing of mouse hearts under pressure overload to identify CF subclusters.
• Genetic manipulation (Myc deletion) in CFs to assess its impact on cardiac function and fibrosis.
• Gene expression analysis (MYC, CXCL1) in mouse and human CFs.
• Assessment of CXCL1's effect on cardiomyocyte contractility and the efficacy of blocking the CXCL1-CXCR2 axis in HF models.

Main Results:

• A specific CF subcluster expressing the transcription factor Myc was identified in HF mouse hearts.
• Deletion of Myc in CFs improved cardiac function without altering fibrosis levels.
• MYC directly regulates CXCL1 expression, which is upregulated in HF-specific CFs.
• The CXCL1-CXCR2 signaling pathway impairs cardiomyocyte contractility and contributes to HF.
• Human failing heart CFs also exhibit elevated MYC and CXCL1 expression.

Conclusions:

• HF-specific cardiac fibroblasts contribute to HF pathogenesis through the MYC-CXCL1-CXCR2 signaling pathway.
• This pathway represents a novel therapeutic target for heart failure, extending beyond cardiomyocyte-centric approaches.
• Targeting CFs and their secreted factors offers a promising new strategy for HF treatment.