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The pathway connecting APJ to PI3K is still unknown. As other GPCR ligands act through transactivation of epidermal growth factor receptor (EGFR) <jats:italic>via<\/jats:italic> a matrix metalloproteinase (MMP) or Src kinase, we investigated whether EGFR transactivation is involved in the following three features of apelin\u2010induced cardioprotection: limitation of infarct size, suppression of contracture and improvement of post\u2010ischaemic contractile recovery.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>Isolated rat hearts underwent 30\u00a0min of global ischaemia and 2\u00a0h of reperfusion. Apelin (0.5\u00a0\u03bc<jats:sc>m<\/jats:sc>) was infused during the first 20\u00a0min of reperfusion. EGFR, MMP or Src was inhibited to study the pathway connecting APJ to PI3K. Key components of RISK pathway, namely PI3K, guanylyl cyclase or mitochondrial K<jats:sup>+<\/jats:sup>\u2010ATP channels, were also inhibited. Apelin\u2010induced EGFR and phosphatase and tensing homolog (PTEN) phosphorylation were assessed. Left ventricular pressure and infarct size were measured.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Apelin\u2010induced reductions in infarct size and myocardial contracture were prevented by the inhibition of EGFR, Src, MMP or RISK pathway. The involvement of EGFR was confirmed by its phosphorylation. However, neither direct EGFR nor MMP inhibition affected apelin\u2010induced improvement of early post\u2010ischaemic contractile recovery, which was suppressed by Src and RISK inhibitors only. Apelin also increased PTEN phosphorylation, which was removed by Src inhibition.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>While EGFR and MMP limit infarct size and contracture, Src or RISK pathway inhibition suppresses the three features of cardioprotection. Src does not only transactivate EGFR, but also inhibits PTEN by phosphorylation thus playing a crucial role in apelin\u2010induced cardioprotection.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.12924","type":"journal-article","created":{"date-parts":[[2017,7,27]],"date-time":"2017-07-27T08:06:43Z","timestamp":1501142803000},"source":"Crossref","is-referenced-by-count":30,"title":["Apelin\u2010induced cardioprotection against ischaemia\/reperfusion injury: roles of epidermal growth factor and Src"],"prefix":"10.1111","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2057-3864","authenticated-orcid":false,"given":"A.","family":"Folino","sequence":"first","affiliation":[{"name":"Department of Clinical and Biological Sciences University of Turin Orbassano Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L.","family":"Accomasso","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences University of Turin Orbassano Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C.","family":"Giachino","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences University of Turin Orbassano Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P. 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