ANTXR1/TEM8 Blockade Prevents Heart Failure through Suppression of TGF-ß 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 TGFß-mediated extracellular matrix remodeling. Thus, ANTXR1 function during heart failure is both maladaptive and druggable, providing promising new avenues for therapeutic intervention. Overall design: AngII/PE study: The mice were implanted with osmotic pump containing angiotensin II/phenylephrine (ANG II/PE) to induced hypertension heart disease. MI study: The mice were subjected to permanent ligation of left anterior descending artery to cause ischemia in the left ventricle of the heart. T8Ab: Anti-Antxr1 antibody that was injected to mice through intraperitoneal injection. The high quality single cells were purified from each group using Multi Tissue Dissociation Kit 2 (Miltenyi) and scRNA-seq library were prepared using 10x genomics kits and sequenced using NovaSeq 6000. Finally all the scRNA-seq dataset were analyzed using Seurat program.