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It is critical to limit the profibrotic remodeling and activate the reparative remodeling phase to limit cardiac diastolic dysfunction. Mesenchymal stem cell (MSC) exosomes offer significant protection against ischemia-related systolic dysfunction. Here, we studied if MSC exosomes would offer protection against profibrotic events in mouse hearts subjected to acute ischemia [1 h left coronary artery (LCA) occlusion] or chronic ischemia (7 days LCA occlusion). After acute ischemia, there was activation of inflammatory signals, more in the peri-infarct than in the infarct area, in the saline (vehicle)-treated mice. At the same time, there was expression of cardiac remodeling signals (vimentin, collagens-1 and -3, and fibronectin), more in the infarct area. Treatment with MSC exosomes before LCA ligation suppressed inflammatory signals during acute and chronic ischemia. Furthermore, exosome treatment promoted pro-reparative cardiac extracellular matrix (ECM) remodeling in both infarct and peri-infarct areas by suppressing fibronectin secretion and by modulating collagen secretion to reduce fibrotic scar formation through altered cellular signaling pathways. Proteomics study revealed intense expression of IL-1\u03b2 and activation of profibrotic signals in the saline-treated hearts and their suppression in MSC exosome-treated hearts. To our knowledge, this is the first report on the infarct and peri-infarct area proteomics of ischemic mice hearts to explain MSC exosome-mediated suppression of scar formation in the ischemic mouse hearts. <\/jats:p>","DOI":"10.1152\/ajpregu.00124.2021","type":"journal-article","created":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T12:00:39Z","timestamp":1629892839000},"page":"R639-R654","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Proteomic basis of modulation of postischemic fibrosis by MSC exosomes"],"prefix":"10.1152","volume":"321","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9764-3317","authenticated-orcid":true,"given":"Rajshekhar A.","family":"Kore","sequence":"first","affiliation":[{"name":"Cardiology Section, Central Arkansas Veterans Healthcare System, and         the University of Arkansas for Medical Sciences, Little Rock, 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