@article {26553,
	title = {Levosimendan prevents doxorubicin-induced cardiotoxicity in time- and dose-dependent manner: implications for inotropy},
	journal = {Cardiovasc ResCardiovasc ResCardiovasc Res},
	volume = {116},
	number = {3},
	year = {2020},
	note = {Efentakis, PanagiotisVarela, AimiliaChavdoula, EvangeliaSigala, FragiskaSanoudou, DespinaTenta, RoxaneGioti, KaterinaKostomitsopoulos, NikolaosPapapetropoulos, AndreasTasouli, AndronikiFarmakis, DimitriosDavos, Costantinos HKlinakis, ApostolosSuter, ThomasCokkinos, Dennis VIliodromitis, Efstathios KWenzel, PhilipAndreadou, IoannaengResearch Support, Non-U.S. Gov{\textquoteright}tEngland2019/06/23 06:00Cardiovasc Res. 2020 Mar 1;116(3):576-591. doi: 10.1093/cvr/cvz163.},
	month = {Mar 1},
	pages = {576-591},
	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 mug/kg-cumulative), and DXR+LEVO (acute) (LEVO, 24 mug/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 mug/kg-bolus) for 28 days. Echocardiography was performed in all protocols. To elucidate levosimendan{\textquoteright}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{\textquoteright}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.},
	keywords = {Animals, Antibiotics, Antineoplastic/*toxicity, Calcium Signaling, Calcium-Binding Proteins/genetics/metabolism, Cardiotoxicity, Cardiovascular Agents/*pharmacology, Cells, Cultured, control, Cyclic AMP-Dependent Protein Kinases/metabolism, Cyclic AMP/metabolism, Cyclic GMP-Dependent Protein Kinases/metabolism, Cyclic GMP/metabolism, Dose-Response Relationship, Drug, Doxorubicin/*toxicity, Female, Heart Diseases/chemically induced/metabolism/physiopathology/*prevention \&, Male, Mammary Neoplasms, Experimental/*drug therapy/metabolism/pathology, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Myocardial Contraction/*drug effects, Myocytes, Cardiac/*drug effects/metabolism/pathology, Nitric Oxide Synthase Type III/metabolism, Proto-Oncogene Proteins c-akt/metabolism, Rats, Wistar, Simendan/*pharmacology, Time Factors},
	isbn = {1755-3245 (Electronic)0008-6363 (Linking)},
	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.}
}
