@article{3077697,
    title = "Levosimendan prevents doxorubicin-induced cardiotoxicity in time- and dose-dependent manner: Implications for inotropy",
    author = "Efentakis, P. and Varela, A. and Chavdoula, E. and Sigala, F. and Sanoudou, D. and Tenta, R. and Gioti, K. and Kostomitsopoulos, N. and Papapetropoulos, A. and Tasouli, A. and Farmakis, D. and Davos, C.H. and Klinakis, A. and Suter, T. and Cokkinos, D.V. and Iliodromitis, E.K. and Wenzel, P. and Andreadou, I.",
    journal = "Cardiovascular Research",
    year = "2020",
    volume = "116",
    number = "3",
    pages = "576-591",
    publisher = "Oxford University Press",
    issn = "0008-6363, 1755-3245",
    doi = "10.1093/cvr/cvz163",
    keywords = "beta tubulin;  cyclic AMP;  cyclic AMP dependent protein kinase;  cyclic GMP;  dobutamine;  doxorubicin;  endothelial nitric oxide synthase;  inducible nitric oxide synthase;  levosimendan;  manganese superoxide dismutase;  milrinone;  n [2 (4 bromocinnamylamino)ethyl] 5 isoquinolinesulfonamide;  n(g) nitroarginine methyl ester;  phospholamban;  protein kinase B;  reduced nicotinamide adenine dinucleotide phosphate oxidase;  antineoplastic antibiotic;  calcium binding protein;  cardiovascular agent;  cyclic AMP;  cyclic AMP dependent protein kinase;  cyclic GMP;  cyclic GMP dependent protein kinase;  doxorubicin;  endothelial nitric oxide synthase;  phospholamban;  protein kinase B;  simendan, adult;  animal cell;  animal experiment;  animal model;  animal tissue;  Article;  cardiac muscle cell;  cardiotoxicity;  cell isolation;  cell viability;  chronopharmacology;  controlled study;  dose response;  drug cytotoxicity;  echocardiography;  enzyme inhibition;  female;  fractional shortening;  gene knockout;  heart left ventricle enddiastolic diameter;  heart left ventricle endsystolic diameter;  heart muscle contractility;  heart protection;  histopathology;  in vitro study;  in vivo study;  inotropism;  male;  mouse;  nonhuman;  oxidative stress;  priority journal;  rat;  repeated drug dose;  single drug dose;  129 mouse;  animal;  C57BL mouse;  calcium signaling;  cardiotoxicity;  cell culture;  dose response;  drug effect;  experimental mammary neoplasm;  genetics;  heart contraction;  heart disease;  knockout mouse;  metabolism;  pathology;  pathophysiology;  time factor;  Wistar rat, Animals;  Antibiotics, Antineoplastic;  Calcium Signaling;  Calcium-Binding Proteins;  Cardiotoxicity;  Cardiovascular Agents;  Cells, Cultured;  Cyclic AMP;  Cyclic AMP-Dependent Protein Kinases;  Cyclic GMP;  Cyclic GMP-Dependent Protein Kinases;  Dose-Response Relationship, Drug;  Doxorubicin;  Female;  Heart Diseases;  Male;  Mammary Neoplasms, Experimental;  Mice, 129 Strain;  Mice, Inbred C57BL;  Mice, Knockout;  Myocardial Contraction;  Myocytes, Cardiac;  Nitric Oxide Synthase Type III;  Proto-Oncogene Proteins c-akt;  Rats, Wistar;  Simendan;  Time Factors",
    abstract = "Aims: 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. Methods and results: 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 mg/kg-cumulative), DXR+LEVO (LEVO, 24 μg/kg-cumulative), and DXR+LEVO (acute) (LEVO, 24 μg/kg-bolus) for 14 days. 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-/-) mice were assigned to PLN-/-/Control (N/S-0.9%), PLN-/-/DXR (18 mg/kg), and PLN-/-/DXR+LEVO (ac) for 14 days. Furthermore, female breast cancer-bearing (BC) mice were divided into: Control (normal saline 0.9%, N/S 0.9%), DXR (18 mg/kg), LEVO, and DXR+LEVO (LEVO, 24 μg/kg-bolus) for 28 days. Echocardiography was performed in all protocols. To elucidate levosimendan's 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-/- mice. Levosimendan's 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. Conclusion: Single dose levosimendan prevented doxorubicin cardiotoxicity through a cAMP-PKA-PLN pathway, highlighting the role of inotropy in doxorubicin cardiotoxicity. © 2019 Published on behalf of the European Society of Cardiology. All rights reserved."
}