Τίτλος:
Levosimendan prevents doxorubicin-induced cardiotoxicity in time- and dose-dependent manner: Implications for inotropy
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Συγγραφείς:
Efentakis, P.
Varela, A.
Chavdoula, E.
Sigala, F.
Sanoudou, D.
Tenta, R.
Gioti, K.
Kostomitsopoulos, N.
Papapetropoulos, A.
Tasouli, A.
Farmakis, D.
Davos, C.H.
Klinakis, A.
Suter, T.
Cokkinos, D.V.
Iliodromitis, E.K.
Wenzel, P.
Andreadou, I.
Περιοδικό:
Cardiovascular Research
Εκδότης:
Oxford University Press
Λέξεις-κλειδιά:
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
