Matrix stiffness controls cardiac fibroblast activation through regulating YAP via AT₁ R

Area of Science:

• Cardiovascular Biology
• Mechanobiology
• Biomedical Engineering

Background:

• Cardiac fibrosis, driven by activated cardiac fibroblasts (CFs), leads to heart failure.
• Increased extracellular matrix (ECM) stiffness is a hallmark of fibrotic hearts and promotes CF activation.
• The precise molecular mechanisms by which CFs sense matrix stiffness remain incompletely understood.

Purpose of the Study:

• To identify key molecules involved in sensing matrix stiffness and regulating cardiac fibroblast (CF) activation.
• To elucidate the role of Yes-associated protein (YAP) in mediating matrix stiffness-induced CF activation and cardiac fibrosis.

Main Methods:

• Analysis of YAP expression and localization in native fibrotic cardiac tissues.
• Utilizing mechanically regulated in vitro cell culture models to study CFs on stiff matrices.
• Investigating the effects of YAP knockdown and overexpression on CF activation and fibrogenic responses.
• Exploring the YAP pathway's relationship with angiotensin II type 1 receptor signaling.

Main Results:

• Elevated YAP expression and nuclear localization were observed in fibrotic cardiac tissues.
• Stiff matrices significantly increased YAP expression and nuclear localization in CFs, correlating with enhanced cell activation.
• YAP knockdown attenuated the fibrogenic response, while YAP overexpression promoted CF activation.
• The YAP pathway was identified as a downstream signaling component of the angiotensin II type 1 receptor in CF mechanotransduction.

Conclusions:

• Yes-associated protein (YAP) is a critical mediator of cardiac fibroblast activation and fibrotic responses to matrix stiffness.
• YAP acts as a key mechanotransducer, translating matrix stiffness into pro-fibrotic signaling.
• Targeting the YAP pathway may offer novel therapeutic strategies for treating cardiac fibrosis and related heart failure.