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It participates in infarct size determination in acute myocardial infarction and graft rejection following heart transplantation. We previously showed that P2Y11 exerted an immunosuppressive role in human dendritic cells, modulated cardiofibroblasts\u2019 response to ischemia\/reperfusion <jats:italic>in vitro<\/jats:italic> and delayed graft rejection in an allogeneic heterotopic heart transplantation model. We sought to investigate a possible role of P2Y11 in the cellular response of cardiomyocytes to ischemia\/reperfusion. We subjected human AC16 cardiomyocytes to 5\u2009h hypoxia\/1\u2009h reoxygenation (H\/R). P2Y11R (P2Y11 receptor) selective agonist NF546 and\/or antagonist NF340 were added at the onset of reoxygenation. Cellular damages were assessed by LDH release, MTT assay and intracellular ATP level; intracellular signaling pathways were explored. The role of P2Y11R in mitochondria-derived ROS production and mitochondrial respiration was investigated. <jats:italic>In vitro<\/jats:italic> H\/R injuries were significantly reduced by P2Y11R stimulation at reoxygenation. This protection was suppressed with P2Y11R antagonism. P2Y11R stimulation following H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>-induced oxidative stress reduced mitochondria-derived ROS production and damages through PKC\u03b5 signaling pathway activation. Our results suggest a novel protective role of P2Y11 in cardiomyocytes against reperfusion injuries. Pharmacological post-conditioning targeting P2Y11R could therefore contribute to improve myocardial ischemia\/reperfusion outcomes in acute myocardial infarction and cardiac transplantation.<\/jats:p>","DOI":"10.1038\/s41598-019-48006-6","type":"journal-article","created":{"date-parts":[[2019,8,12]],"date-time":"2019-08-12T10:03:02Z","timestamp":1565604182000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Stimulation of P2Y11 receptor protects human cardiomyocytes against Hypoxia\/Reoxygenation injury and involves PKC\u03b5 signaling pathway"],"prefix":"10.1038","volume":"9","author":[{"given":"Lauriane","family":"Benoist","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"Chadet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thibaud","family":"Genet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudie","family":"Lefort","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Heraud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria D.","family":"Danila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danina M.","family":"Muntean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Baron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0788-8092","authenticated-orcid":false,"given":"Denis","family":"Angoulvant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Babuty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Bourguignon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2407-6387","authenticated-orcid":false,"given":"Fabrice","family":"Ivanes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,8,12]]},"reference":[{"key":"48006_CR1","doi-asserted-by":"publisher","first-page":"1570","DOI":"10.1056\/NEJMra0901217","volume":"361","author":"RS Hotchkiss","year":"2009","unstructured":"Hotchkiss, R. 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