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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE266597 | GEO | 2025/08/21

REPOSITORIES: GEO

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Project description:Ischemic heart failure after acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. We recently reported that activation of a trans-valvular axial-flow pump in the LV and delaying myocardial reperfusion, known as Primary Unloading, limits infarct size by reducing LV wall stress and increasing expression of the cardioprotective cytokine, stromal derived factor 1 alpha (SDF1a). The mechanisms underlying the cardioprotective benefit and sustained effect of Primary Unloading remain poorly understood. We now tested the importance of delayed reperfusion, the functional significance of SDF1a, and the late-term impact on myocardial function and scar size associated with Primary Unloading. Adult male swine were subjected to Primary Reperfusion or Primary Unloading after 90 minutes of left anterior descending artery occlusion. Compared to Primary Reperfusion, 30 minutes of Primary Unloading was necessary and sufficient prior to reperfusion to limit infarct size. Primary Unloading was associated with a global shift in gene expression within the infarct zone favoring cardioprotection. Compared to Primary Reperfusion, Primary Unloading for 30 minutes preserved SDF1a protein levels without changing SDF1a mRNA levels within the infarct zone and further promoted a shift towards anti-apoptotic signaling within the infarct zone. Primary Unloading reduced activity levels of proteases known to degrade SDF1a and blocking the SDF1a receptor, CXCR4, attenuated the cardioprotective effect of Primary Unloading. Primary Unloading further reduced LV scar size, improved cardiac function, limited expression of markers associated with heart failure and maladaptive remodeling within the non-infarct zone 28 days after acute myocardial infarction. In conclusion, we introduce that Primary Unloading for 30 minutes before, not after reperfusion limits infarct size, increases SDF1a levels within the infarct zone, and results in a durable reduction in LV scar size, improved cardiac function, and limits markers of heart failure and maladaptive remodeling 28 days after AMI.

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

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