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Hepatocyte growth factor (HGF) protects cardiomyocytes from injury, but its effective use is compromised by low biodistribution. In this study, we have investigated whether the activation of the HGF receptor\u2014encoded by the <jats:italic>Met<\/jats:italic> gene\u2014by an agonist monoclonal antibody (mAb) could protect against doxorubicin\u2010induced cardiotoxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The mAb (5 mg\u00b7kg<jats:sup>\u22121<\/jats:sup>) was injected in vivo into C57BL\/6J mice, before doxorubicin (three doses of 7 mg\u00b7kg<jats:sup>\u22121<\/jats:sup>). Cardiac functions were evaluated through MRI after treatment termination. Heart histological staining and mRNA levels of genes associated with heart failure (<jats:italic>Acta1<\/jats:italic> and <jats:italic>Nppa<\/jats:italic>), inflammation (<jats:italic>IL\u20106<\/jats:italic>), and fibrosis (<jats:italic>Ctgf<\/jats:italic>, <jats:italic>Col1a2<\/jats:italic>, <jats:italic>Timp1<\/jats:italic>, and <jats:italic>Mmp9<\/jats:italic>) were assessed. MAb (100 nM) was administered in vitro to H9c2 cardiomyoblasts before addition of doxorubicin (25 \u03bcM). DDR and apoptosis markers were evaluated by quantitative western blotting, flow cytometry, and immunofluorescence. Stattic was used for pharmacological inactivation of STAT3.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>In vivo, administration of the mAb alleviated doxorubicin\u2010induced cardiac dysfunction and fibrosis. In vitro, mAb mimicked the response to HGF by (a) inhibiting histone H2AX phosphorylation at S139, (b) quenching the expression of the DNA repair enzyme PARP1, and (c) reducing the proteolytic activation of caspase 3. The MET\u2010driven cardioprotection involved, at least in vitro, the phosphorylation of STAT3.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>The MET agonist mAb provides a new tool for cardioprotection against anthracycline cardiotoxicity.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15039","type":"journal-article","created":{"date-parts":[[2020,3,5]],"date-time":"2020-03-05T05:54:10Z","timestamp":1583387650000},"page":"3107-3122","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Activation of the <scp>MET<\/scp> receptor attenuates doxorubicin\u2010induced cardiotoxicity in vivo and in vitro"],"prefix":"10.1111","volume":"177","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7404-1356","authenticated-orcid":false,"given":"Simona","family":"Gallo","sequence":"first","affiliation":[{"name":"Candiolo Cancer Institute FPO\u2010IRCCS  Candiolo (TO) Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Spilinga","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute FPO\u2010IRCCS  Candiolo (TO) Italy"},{"name":"Department of Oncology University of Turin  Turin Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Albano","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute FPO\u2010IRCCS  Candiolo (TO) Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Ferrauto","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences University of Turin  Turin Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enza","family":"Di Gregorio","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences University of Turin  Turin Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Casanova","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute FPO\u2010IRCCS  Candiolo (TO) Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Balmativola","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute FPO\u2010IRCCS  Candiolo (TO) Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Bonzano","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute FPO\u2010IRCCS  Candiolo (TO) Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2620-9083","authenticated-orcid":false,"given":"Carla","family":"Boccaccio","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute FPO\u2010IRCCS  Candiolo (TO) Italy"},{"name":"Department of Oncology University of Turin  Turin Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Sapino","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute FPO\u2010IRCCS  Candiolo (TO) Italy"},{"name":"Department of Medical Sciences University of Turin  Turin Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo Maria","family":"Comoglio","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute FPO\u2010IRCCS  Candiolo (TO) Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3410-947X","authenticated-orcid":false,"given":"Tiziana","family":"Crepaldi","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute FPO\u2010IRCCS  Candiolo (TO) Italy"},{"name":"Department of Oncology University of Turin  Turin Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,5,29]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14751"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14752"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14747"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14112"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(96)07015-8"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2013.08.008"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnmrs.2015.03.001"},{"key":"e_1_2_11_9_1","first-page":"4347","article-title":"Expression of phosphorylated histone H2AX as a surrogate of cell killing by drugs that create DNA double\u2010strand breaks","volume":"63","author":"Ban\u00e1th J. 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