Abstract
The extra-cellular-matrix (ECM) composition of scar tissue after myocardial infarction (MI)has been largely investigated. Although fibronectin and collagen are favorable for newmyocyte formation, other components that may increase the scar stiffness and reducethe remodeling of the ischemic area, remain to be identified. Our preliminary studiesidentified primary Serum Amyloid A3 (SAA3) extracellular accumulation that maycontribute to the chronic alteration of the ischemic myocardium’s scar. Specifichistological staining such as thioflavin and Congo red, showed amyloid deposition inmouse hearts 1 month after MI; furthermore, immunohistochemistry for SAA3 detectedthe deposition of the misfolded protein alongside fibronectin and collagen. Serum amyloidamyloidosis (AA) is characterized by deposition of hepatic misfolded protein and SAA3 isthe only amyloid protein that is released locally after inflammation, mostly bymesenchymal progenitor cells. We have reported earlier that two days after MI, a cohortof mesenchymal cells begin to de novo express Podoplanin (PDPN), a plateletaggregation-inducing type I transmembrane glycoprotein, as a signal of activation.PDPN+ cells, in addition to cytokines, release extracellular vesicles including exosomes(Exo) as major paracrine entities driving intercellular communications in homeostasis anddisease. Exo derived from activated PDPN+ cells isolated from MI hearts highly expressSAA3 and injection of activated PDPN+ cell Exo in uninjured healthy mouse hearts leadsto recruitment of immune cells, an extended epicardial fibrosis and amyloidosis with asubsequent impairment in the contractility and increase of the end systolic volumes anddiameters. SAA3 binds Toll-like receptors, and in vitro treatment of bone marrow derivedmonocytes either with PDPN+ cells derived Exo or recombinant SAA3, activated themtowards pro-inflammatory phenotype on contrary these stimuli failed to activate TLR2knocked out monocytes showing an impairment in the expression of major cytokine,chemokine and pro inflammatory markers. Thus, PDPN+ cells in the ischemic heartrelease SAA3 through Exo prolonging inflammation and macrophage recruitment viaTLR2 and contribute to amyloidosis after MI.
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