Podoplanin-positive cell-derived small extracellular vesicles contribute to cardiac amyloidosis after myocardial infarction
Cardiac amyloidosis is a secondary phenomenon of an already pre-existing chronic condition. Whether cardiac amyloidosis represents one of the complications post myocardial infarction (MI) has yet to be fully understood. Here, we show that amyloidosis occurs after MI and that amyloid fibers are composed of macrophage-derived serum amyloid A 3 (SAA3) monomers. SAA3 overproduction in macrophages is triggered by exosomal communication from cardiac stromal cells (CSCs), which, in response to MI, activate the expression of a platelet aggregation-inducing type I transmembrane glycoprotein, Podoplanin (PDPN). CSC<sup>PDPN+</sup>-derived small extracellular vesicles (sEVs) are enriched in SAA3, and exosomal SAA3 engages with macrophage by Toll-like receptor 2, triggering overproduction with consequent impaired clearance and aggregation of SAA3 monomers into rigid fibers. SAA3 amyloid deposits reduce cardiac contractility and increase scar stiffness. Inhibition of SAA3 aggregation by retro-inverso D-peptide, specifically designed to bind SAA3 monomers, prevents the deposition of SAA3 amyloid fibrils and improves heart function post MI.
Authors
- Ulrich H. E. Hansmann (ORCID: https://orcid.org/0000-0002-0700-4835)
- Elvira Forte (ORCID: https://orcid.org/0000-0002-5555-9122)
- Charan Thej
- Rajika Roy (ORCID: https://orcid.org/0000-0001-9394-3224)
- Raj Kishore (ORCID: https://orcid.org/0000-0002-8168-3004)
- Çağla Tükel (ORCID: https://orcid.org/0000-0001-7073-0226)
- Werner Koch
- Erhe Gao (ORCID: https://orcid.org/0000-0002-5151-7857)
- Darukeshwara Joladarashi (ORCID: https://orcid.org/0000-0002-9466-9228)
- Maria Cimini (ORCID: https://orcid.org/0000-0001-5414-6257)
- Cindy Benedict (ORCID: https://orcid.org/0000-0001-8380-161X)
- Ajit Magadum (ORCID: https://orcid.org/0000-0001-7298-8255)
- Andrew D. Chesney (ORCID: https://orcid.org/0000-0001-7694-9894)
- May Truongcao
- Carolina González (ORCID: https://orcid.org/0000-0002-1645-7190)
- Tao Wang (ORCID: https://orcid.org/0000-0002-3475-6354)
- Vandana Mallaredy
Institutions
- Duke University (US)
- Jackson Laboratory (US)
- Temple University (US)
- University of Oklahoma (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115408
- Primary Topic
- Lymphatic System and Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Heart Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases