Adamts1 Exacerbates Post-Myocardial Infarction Scar Formation via Mechanosensing of Integrin α8

Area of Science:

• Cardiovascular Biology
• Extracellular Matrix Biology
• Mechanobiology

Background:

• Myocardial infarction (MI) leads to cardiac remodeling and scar formation, impacting patient outcomes.
• Pathological scar formation mechanisms post-MI are not fully understood.
• Endothelial cell-specific ADAMTS1 is upregulated after MI.

Purpose of the Study:

• To investigate the role of ADAMTS1 in cardiac fibroblast activation and post-infarction remodeling.
• To elucidate the novel mechanotransduction pathway involving ADAMTS1 and integrin α8 (ITGα8).

Main Methods:

• Utilized endothelial cell-specific ADAMTS1 overexpression and knockout mouse models.
• Employed cardiac fibroblast-specific ITGα8 deletion models.
• Performed tunable-stiffness hydrogel experiments, proteomic, and functional analyses.

Main Results:

• ADAMTS1 overexpression worsened cardiac dysfunction and increased scar size; ADAMTS1 deficiency was cardioprotective.
• ADAMTS1 modulated extracellular matrix stiffness via proteoglycan cleavage, activating ITGα8 mechanosensing in fibroblasts.
• ITGα8 deficiency rescued ADAMTS1-induced cardiac dysfunction and reduced scar formation.

Conclusions:

• Identified a novel ADAMTS1-ITGα8 mechanotransduction pathway regulating cardiac fibroblast activation post-MI.
• This pathway represents a potential therapeutic target for optimizing cardiac remodeling after myocardial infarction.