Document Type

Article

Publication Date

3-25-2025

Publication Title

Cell Rep

Keywords

JGM, Animals, Myocardial Infarction, Extracellular Vesicles, Amyloidosis, Membrane Glycoproteins, Mice, Serum Amyloid A Protein, Humans, Macrophages, Mice, Inbred C57BL, Male, Toll-Like Receptor 2, Stromal Cells, Podoplanin

JAX Source

Cell Rep. 2025;44(3):115408.

Volume

44

Issue

3

First Page

115408

Last Page

115408

ISSN

2211-1247

PMID

40056419

DOI

https://doi.org/10.1016/j.celrep.2025.115408

Abstract

Cardiac amyloidosis is a secondary phenomenon of an already pre-existing chronic condition. Whether car- diac amyloidosis represents one of the complications post myocardial infarction (MI) has yet to be fully under- stood. 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 PDPN+ -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 stiff- ness. Inhibition of SAA3 aggregation by retro-inverso D-peptide, specifically designed to bind SAA3 mono- mers, prevents the deposition of SAA3 amyloid fibrils and improves heart function post MI.

Comments

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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