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Here we tested whether statin treatment affects resident endogenous cardiac stem\/progenitor cell (CSC) activation in vitro and in vivo after myocardial infarction (MI). Statins (Rosuvastatin, Simvastatin and Pravastatin) significantly increased CSC expansion in vitro as measured by both BrdU incorporation and cell growth curve. Additionally, statins increased CSC clonal expansion and cardiosphere formation. The effects of statins on CSC growth and differentiation depended on Akt phosphorylation. Twenty-eight days after myocardial infarction by permanent coronary ligation in rats, the number of endogenous CSCs in the infarct border zone was significantly increased by Rosuvastatin-treatment as compared to untreated controls. Additionally, commitment of the activated CSCs into the myogenic lineage (c-kitpos\/Gata4pos CSCs) was increased by Rosuvastatin administration. Accordingly, Rosuvastatin fostered new cardiomyocyte formation after MI. Finally, Rosuvastatin treatment reversed the cardiomyogenic defects of CSCs in c-kit haploinsufficient mice, increasing new cardiomyocyte formation by endogenous CSCs in these mice after myocardial infarction. In summary, statins, by sustaining Akt activation, foster CSC growth and differentiation in vitro and in vivo. The activation and differentiation of the endogenous CSC pool and consequent new myocyte formation by statins improve myocardial remodeling after coronary occlusion in rodents. Similar effects might contribute to the beneficial effects of statins on human cardiovascular diseases.<\/jats:p>","DOI":"10.3390\/ijms21217927","type":"journal-article","created":{"date-parts":[[2020,10,26]],"date-time":"2020-10-26T10:38:35Z","timestamp":1603708715000},"page":"7927","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Statins Stimulate New Myocyte Formation After Myocardial Infarction by Activating Growth and Differentiation of the Endogenous Cardiac Stem Cells"],"prefix":"10.3390","volume":"21","author":[{"given":"Eleonora","family":"Cianflone","sequence":"first","affiliation":[{"name":"Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donato","family":"Cappetta","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania \u201cL. Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Mancuso","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1661-5419","authenticated-orcid":false,"given":"Jolanda","family":"Sabatino","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiola","family":"Marino","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariangela","family":"Scalise","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Albanese","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Salatino","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8145-3623","authenticated-orcid":false,"given":"Elvira Immacolata","family":"Parrotta","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6313-1866","authenticated-orcid":false,"given":"Giovanni","family":"Cuda","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"De Angelis","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania \u201cL. Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liberato","family":"Berrino","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania \u201cL. Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania \u201cL. Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1197-3612","authenticated-orcid":false,"given":"Bernardo","family":"Nadal-Ginard","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Torella","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konrad","family":"Urbanek","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/S0092-8674(03)00687-1","article-title":"Adult Cardiac Stem Cells Are Multipotent and Support Myocardial Regeneration","volume":"114","author":"Beltrami","year":"2003","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1089\/ars.2011.4179","article-title":"Cardiac aging: From molecular mechanisms to significance in human health and disease","volume":"16","author":"Dai","year":"2012","journal-title":"Antioxid. 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