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

-Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide, with post-infarction cardiac remodeling, particularly excessive scar formation, representing a critical determinant of patient outcomes. However, the mechanistic pathways governing pathological scar formation remain incompletely understood. Here, we demonstrate that ADAMTS1 (A Disintegrin and Metalloproteinase with Thrombospondin Motifs 1), significantly upregulated in endothelial cells (ECs) following MI, plays a pivotal role in regulating cardiac fibroblast activation through a novel mechanotransduction pathway involving integrin α8 (ITGα8). Using EC-specific ADAMTS1 overexpression and knockout mice combined with cardiac fibroblast-specific ITGα8 deletion models, we found that ADAMTS1 overexpression exacerbates cardiac dysfunction and increases scar size, while ADAMTS1 deficiency provides cardioprotection. Mechanistically, ADAMTS1 modulates extracellular matrix stiffness through proteoglycan (PG) cleavage rather than direct protein interactions, which activates ITGα8 mechanosensing specifically in cardiac fibroblasts. Among integrin family members tested, ITGα8 shows selective responsiveness to ADAMTS1-mediated mechanical cues, as confirmed by tunable-stiffness hydrogel experiments and validated through comprehensive proteomic and functional analyses. ITGα8 deficiency rescues ADAMTS1-induced cardiac dysfunction and reduces pathological scar formation. These findings reveal a previously unrecognized ADAMTS1-ITGα8 mechanotransduction pathway, representing a promising therapeutic target for optimizing post-infarction cardiac remodeling.