ANTXR1/TEM8 Blockade Prevents Heart Failure through Suppression of TGF-β Signaling

Heart disease, a leading cause of mortality worldwide, is in urgent need of improved therapies. Here, ANTXR1/TEM8, a transmembrane protein required for collagen uptake, was found to promote heart failure. In preclinical intervention studies, genetic disruption of Antxr1 prevented heart deterioration following acute myocardial infarction, a phenotype that was mirrored by treatment with ANTXR1 neutralizing antibodies. ANTXR1 pharmacologic blockade also improved heart function in models of pressure overload and obesity-induced heart disease with preserved ejection fraction. Exploratory studies to further unravel the mechanism, including single cell transcriptomics, revealed a striking ANTXR1-antibody driven improvement in post-infarct scar formation followed by attenuation of late-stage, chronic TGFβ-mediated extracellular matrix remodeling. Thus, ANTXR1 function during heart failure is both maladaptive and druggable, providing promising new avenues for therapeutic intervention.