{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T04:20:18Z","timestamp":1780374018418,"version":"3.54.1"},"reference-count":57,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2019,6,22]],"date-time":"2019-06-22T00:00:00Z","timestamp":1561161600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"EU-CARDIOPROTECTION COST-Action","award":["CA16225"],"award-info":[{"award-number":["CA16225"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Levosimendan (LEVO) a clinically-used inodilator, exerts multifaceted cardioprotective effects. Case-studies indicate protection against doxorubicin (DXR)-induced cardiotoxicity, but this effect remains obscure. We investigated the effect and mechanism of different regimens of levosimendan on sub-chronic and chronic doxorubicin cardiotoxicity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Based on preliminary in vivo experiments, rats serving as a sub-chronic model of doxorubicin-cardiotoxicity and were divided into: Control (N\/S-0.9%), DXR (18\u2009mg\/kg-cumulative), DXR+LEVO (LEVO, 24\u2009\u03bcg\/kg-cumulative), and DXR+LEVO (acute) (LEVO, 24\u2009\u03bcg\/kg-bolus) for 14\u2009days. Protein kinase-B (Akt), endothelial nitric oxide synthase (eNOS), and protein kinase-A and G (PKA\/PKG) pathways emerged as contributors to the cardioprotection, converging onto phospholamban (PLN). To verify the contribution of PLN, phospholamban knockout (PLN\u2212\/\u2212) mice were assigned to PLN\u2212\/\u2212\/Control (N\/S-0.9%), PLN\u2212\/\u2212\/DXR (18\u2009mg\/kg), and PLN\u2212\/\u2212\/DXR+LEVO (ac) for 14\u2009days. Furthermore, female breast cancer-bearing (BC) mice were divided into: Control (normal saline 0.9%, N\/S 0.9%), DXR (18\u2009mg\/kg), LEVO, and DXR+LEVO (LEVO, 24\u2009\u03bcg\/kg-bolus) for 28\u2009days. Echocardiography was performed in all protocols. To elucidate levosimendan\u2019s cardioprotective mechanism, primary cardiomyocytes were treated with doxorubicin or\/and levosimendan and with N omega-nitro-L-arginine methyl ester (L-NAME), DT-2, and H-89 (eNOS, PKG, and PKA inhibitors, respectively); cardiomyocyte-toxicity was assessed. Single bolus administration of levosimendan abrogated DXR-induced cardiotoxicity and activated Akt\/eNOS and cAMP-PKA\/cGMP-PKG\/PLN pathways but failed to exert cardioprotection in PLN\u2212\/\u2212 mice. Levosimendan\u2019s cardioprotection was also evident in the BC model. Finally, in vitro PKA inhibition abrogated levosimendan-mediated cardioprotection, indicating that its cardioprotection is cAMP-PKA dependent, while levosimendan preponderated over milrinone and dobutamine, by ameliorating calcium overload.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Single dose levosimendan prevented doxorubicin cardiotoxicity through a cAMP-PKA-PLN pathway, highlighting the role of inotropy in doxorubicin cardiotoxicity.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvz163","type":"journal-article","created":{"date-parts":[[2019,6,18]],"date-time":"2019-06-18T11:10:25Z","timestamp":1560856225000},"page":"576-591","source":"Crossref","is-referenced-by-count":42,"title":["Levosimendan prevents doxorubicin-induced cardiotoxicity in time- and dose-dependent manner: implications for inotropy"],"prefix":"10.1093","volume":"116","author":[{"given":"Panagiotis","family":"Efentakis","sequence":"first","affiliation":[{"name":"National and Kapodistrian University of Athens, Laboratory of Pharmacology, Faculty of Pharmacy, Panepistimiopolis, Zografou, Athens 15771, Greece"},{"name":"Center of Cardiology, Cardiology 2, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"},{"name":"Center of Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7605-5361","authenticated-orcid":false,"given":"Aimilia","family":"Varela","sequence":"first","affiliation":[{"name":"Biomedical Research Foundation, Academy of Athens, Clinical, Experimental Surgery & Translational Research Center, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelia","family":"Chavdoula","sequence":"first","affiliation":[{"name":"Biomedical Research Foundation, Academy of Athens, Clinical, Experimental Surgery & Translational Research Center, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fragiska","family":"Sigala","sequence":"first","affiliation":[{"name":"First Department of Surgery, National and Kapodistrian University of Athens Medical School, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Despina","family":"Sanoudou","sequence":"first","affiliation":[{"name":"4th Department of Internal Medicine, Clinical Genomics and Pharmacogenomics Unit, \u201cAttikon\u201d Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4867-6945","authenticated-orcid":false,"given":"Roxane","family":"Tenta","sequence":"first","affiliation":[{"name":"School of Health Sciences and Education, Department of Nutrition and Dietetics, Harokopio University, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katerina","family":"Gioti","sequence":"first","affiliation":[{"name":"School of Health Sciences and Education, Department of Nutrition and Dietetics, Harokopio University, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4787-5106","authenticated-orcid":false,"given":"Nikolaos","family":"Kostomitsopoulos","sequence":"first","affiliation":[{"name":"Biomedical Research Foundation, Academy of Athens, Clinical, Experimental Surgery & Translational Research Center, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4253-5930","authenticated-orcid":false,"given":"Andreas","family":"Papapetropoulos","sequence":"first","affiliation":[{"name":"National and Kapodistrian University of Athens, Laboratory of Pharmacology, Faculty of Pharmacy, Panepistimiopolis, Zografou, Athens 15771, Greece"},{"name":"Biomedical Research Foundation, Academy of Athens, Clinical, Experimental Surgery & Translational Research Center, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Androniki","family":"Tasouli","sequence":"first","affiliation":[{"name":"Onassis Cardiac Surgery Center, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Farmakis","sequence":"first","affiliation":[{"name":"Second Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Athens University Hospital \u201cAttikon\u201d, Athens, Greece"},{"name":"School of Medicine, European University of Cyprus, Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0321-7569","authenticated-orcid":false,"given":"Costantinos H","family":"Davos","sequence":"first","affiliation":[{"name":"Biomedical Research Foundation, Academy of Athens, Clinical, Experimental Surgery & Translational Research Center, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apostolos","family":"Klinakis","sequence":"first","affiliation":[{"name":"Biomedical Research Foundation, Academy of Athens, Clinical, Experimental Surgery & Translational Research Center, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Suter","sequence":"first","affiliation":[{"name":"Department of Cardiology, Bern University Hospital, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis V","family":"Cokkinos","sequence":"first","affiliation":[{"name":"Biomedical Research Foundation, Academy of Athens, Clinical, Experimental Surgery & Translational Research Center, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Efstathios K","family":"Iliodromitis","sequence":"first","affiliation":[{"name":"Second Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Athens University Hospital \u201cAttikon\u201d, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5397-2781","authenticated-orcid":false,"given":"Philip","family":"Wenzel","sequence":"first","affiliation":[{"name":"Center of Cardiology, Cardiology 2, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany"},{"name":"Center of Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, 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