P. Efentakis, A. Varela, E. Chavdoula
Mar 1, 2020
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Influential Citations
29
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Journal
Cardiovascular research
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, 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 (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 L-NAME, DT-2 and H-89 (eNOS, PKG and PKA inhibitors, respectively); cardiomyocyte-toxicity was assessed. Single-bolus administration of levosimendan abrogated doxorubicin-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 Ca2+-overload. CONCLUSIONS Single-dose levosimendan prevented doxorubicin cardiotoxicity through a cAMP-PKA-phospholamban pathway, highlighting the role of inotropy in doxorubicin cardiotoxicity.