Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload

Area of Science:

• Cardiovascular Biology
• Cell Biology
• Molecular Cardiology

Background:

• Cardiac fibroblasts are the most abundant heart cells, interacting with cardiomyocytes.
• Their role in cardiac hypertrophy and failure has been considered secondary.
• The specific contribution of fibroblasts to cardiac responses to stress is not fully understood.

Purpose of the Study:

• To investigate the essential role of cardiac fibroblasts in myocardial adaptive responses to pressure overload.
• To determine the involvement of Krüppel-like factor 5 (KLF5) in fibroblast-mediated cardiac responses.
• To explore the therapeutic potential of targeting cardiac fibroblast function in heart failure.

Main Methods:

• Utilized mouse models with specific gene deletions (Klf5) in cardiac fibroblasts and cardiomyocytes.
• Applied pressure overload models of varying intensities (moderate and high).
• Analyzed cardiac fibrosis, hypertrophy, and heart failure progression.
• Investigated the molecular mechanism involving KLF5, Igf1, and IGF-1 signaling.

Main Results:

• Cardiac fibroblast-specific Klf5 deletion ameliorated cardiac hypertrophy and fibrosis in response to moderate pressure overload.
• Cardiomyocyte-specific Klf5 deletion did not affect hypertrophic responses.
• High-intensity pressure overload led to severe heart failure and early death in mice with Klf5-null fibroblasts.
• KLF5 in fibroblasts activates Igf1, which mediates paracrine hypertrophic responses in cardiomyocytes.
• IGF-1 signaling is essential for cardioprotective responses.

Conclusions:

• Cardiac fibroblasts are essential for the protective and hypertrophic myocardial response to pressure overload.
• The transcription factor KLF5 in cardiac fibroblasts plays a critical role in this adaptive response.
• KLF5-mediated activation of IGF-1 signaling in fibroblasts is a key mechanism.
• Modulating cardiac fibroblast function, potentially via KLF5, represents a novel therapeutic strategy for heart failure.