ANTXR1 blockade enhances cardiac function in preclinical models of heart failure
Heart disease, a leading cause of mortality worldwide, is in urgent need of improved therapies. Fibrosis, an accumulation of collagen-rich extracellular matrix in response to injury, is a hallmark of heart disease, but clinical agents that can interfere with the fibrotic pathway do not yet exist. Here we show that ANTXR1/TEM8, a pathology-induced transmembrane protein required for collagen removal, exacerbates injury in multiple models of heart failure. Genetic disruption of Antxr1 and treatment with human neutralizing antibodies prevented heart deterioration following acute myocardial infarction. ANTXR1 pharmacological blockade also improved heart function in models of pressure overload and obesity-induced heart disease with preserved ejection fraction. Improved heart function was accompanied by enhanced exercise tolerance. Mechanistic studies revealed an ANTXR1-antibody-driven improvement in post-infarct scar formation followed by attenuation of late-stage, chronic TGFβ-mediated extracellular matrix remodeling. Thus, ANTXR1-mediated collagen turnover during heart failure is both maladaptive and druggable, providing avenues for therapeutic intervention.
Authors
- Darren A. Yuen (ORCID: https://orcid.org/0000-0002-0054-6607)
- Daeho So (ORCID: https://orcid.org/0000-0002-6192-6179)
- Lino Tessarollo (ORCID: https://orcid.org/0000-0001-6420-772X)
- Francesco Tomassoni‐Ardori (ORCID: https://orcid.org/0000-0002-8824-3693)
- Sudhirkumar Yanpallewar (ORCID: https://orcid.org/0000-0001-5929-4822)
- Mary Beth Hilton
- Krish C. Dewan (ORCID: https://orcid.org/0000-0001-6611-1422)
- Liping Yang (ORCID: https://orcid.org/0000-0002-9011-0443)
- Guojun Yu (ORCID: https://orcid.org/0000-0003-2126-1827)
- Ryan T. Gross (ORCID: https://orcid.org/0000-0003-4849-0371)
- Jodi Becker
- Brad St. Croix (ORCID: https://orcid.org/0000-0002-6246-0374)
- James M. Dunleavey (ORCID: https://orcid.org/0000-0003-1069-0378)
- Nicola Boccella (ORCID: https://orcid.org/0000-0002-5854-9093)
- Steven Seaman (ORCID: https://orcid.org/0000-0003-3349-3334)
- Pradip Bajgain (ORCID: https://orcid.org/0000-0002-4719-8451)
- Dawn E. Bowles (ORCID: https://orcid.org/0000-0002-2781-1300)
- Jaewon Lee (ORCID: https://orcid.org/0000-0003-2267-6717)
- Karen Morris (ORCID: https://orcid.org/0000-0003-4900-9957)
- Yang Feng (ORCID: https://orcid.org/0009-0001-6579-4628)
- Kuo-Sheng Hsu
- Niza Borchin
Institutions
- Leidos (United States) (US)
- St. Michael's Hospital (CA)
- National Institutes of Health (US)
- Duke University (US)
- Angiogenesis Foundation (US)
- National Cancer Institute (US)
- Center for Cancer Research (US)
Publication Details
- Journal
- Nature Cardiovascular Research
- Published
- 2025-10-02
- DOI
- https://doi.org/10.1038/s44161-025-00725-y
- Citations
- 1
- Primary Topic
- Cardiac Fibrosis and Remodeling
- Type
- article
- Field-Weighted Citation Impact
- 1.39