Podoplanin Positive Cell-derived Extracellular Vesicles Contribute to Cardiac Amyloidosis After Myocardial Infarction

Area of Science:

• Cardiovascular Biology
• Immunology
• Protein Aggregation

Background:

• Amyloidosis is a known complication of chronic diseases, but its role post-myocardial infarction (MI) remains unclear.
• Accumulation of amyloid structures in the heart impairs contractility and can occur after chronic inflammation.
• Mesenchymal stromal cells (MSCs) in the heart acquire Podoplanin (PDPN) post-MI to interact with immune cells.

Purpose of the Study:

• To investigate the mechanism of Serum Amyloid A 3 (SAA3) protein overproduction and amyloidosis post-MI.
• To determine the role of exosomal communication between cardiac MSCs and macrophages in post-MI cardiac remodeling.
• To evaluate a novel peptide-based therapeutic approach for preventing SAA3 aggregation and improving cardiac function.

Main Methods:

• Utilized wild-type and knockout MI mouse models to study amyloidosis mechanisms.
• Characterized in vitro exosomal communication between bone marrow-derived macrophages and activated MSCs post-MI.
• Employed SAA3 and Toll-like receptor 2 (TLR2) deficient mouse models and a retro-inverso D-peptide (DRI-R5S) to inhibit SAA3 aggregation.

Main Results:

• Amyloidosis occurs post-MI, with amyloid fibers composed of macrophage-derived SAA3 monomers.
• Cardiac MSCs expressing PDPN release exosomes enriched in SAA3, activating macrophages via TLR2 and leading to SAA3 overproduction and aggregation.
• Inhibition of SAA3 aggregation with DRI-R5S prevented amyloid deposition, modulated scar formation, and improved heart function post-MI.
• SAA3 amyloidosis was confirmed in failing human heart samples.

Conclusions:

• Post-MI amyloidosis is driven by SAA3 overproduction, triggered by exosomal communication from PDPN+ cardiac MSCs.
• SAA3 aggregation exacerbates cardiac dysfunction by increasing scar rigidity and impairing myocardial contractility.
• Targeting SAA3 aggregation with peptide inhibitors offers a promising therapeutic strategy for scar reversal and functional recovery after MI.