title: Long-acting PDE5 inhibitor tadalafil prevents early doxorubicin-induced left ventricle diastolic dysfunction in juvenile mice: potential role of cytoskeletal proteins.
abstract: The chemotherapeutic use of doxorubicin (Dox) is hindered due to the development of irreversible cardiotoxicity. Specifically, childhood cancer survivors are at greater risk of Dox-induced cardiovascular complications. Because of the potent cardioprotective effect of phosphodiesterase 5 (PDE5) inhibitors, we examined the effect of long-acting PDE5 inhibitor tadalafil (Tada) against Dox cardiotoxicity in juvenile mice. C57BL/6J mice (6 weeks old) were treated with Dox (20 mg/kg, i.v.) and (or) Tada (10 mg/kg daily for 14 days, p.o.). Cardiac function was assessed by echocardiography following 5 and 10 weeks after Dox treatment. The expression of cardiac proteins was examined by Western blot analysis. Dox treatment caused diastolic dysfunction in juvenile mice indicated by increasing the E/E' (early diastolic myocardial velocity to early tissue Doppler velocity) ratio as compared with control at both 5 and 10 weeks after Dox treatment. Co-treatment of Tada and Dox preserved left ventricular diastolic function with reduction of E/E'. Dox treatment decreased the expression of SERCA2 and desmin in the left ventricle; however, only desmin loss was prevented with Tada. Also, Dox treatment increased the expression of myosin heavy chain (MHCβ), which was reduced by Tada. We propose that Tada could be a promising new therapy for improving cardiac function in survivors of childhood cancer.
authors.affiliation: a Division of Pediatric Cardiology, Department of Pediatrics at Children's Hospital of Richmond, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Nagiub
authors.affiliation: b Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Filippone
authors.affiliation: b Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: David
authors.initials: D
authors.lastname: Durrant
authors.affiliation: b Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Anindita
authors.initials: A
authors.lastname: Das
authors.affiliation: b Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Rakesh C
authors.initials: RC
authors.lastname: Kukreja
mesh_terms: D000367:Age Factors; D000818:Animals; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology*; D066126:Cardiotoxicity; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D003893:Desmin / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin; D015150:Echocardiography, Doppler; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000068581:Tadalafil / Q000494:pharmacology*; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D002316:Cardiotonic Agents; D003598:Cytoskeletal Proteins; D003893:Desmin; C551613:Myh7 protein, mouse; D058986:Phosphodiesterase 5 Inhibitors; D000068581:Tadalafil; D004317:Doxorubicin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D018995:Myosin Heavy Chains; C506947:Atp2a2 protein, mouse
keywords: cardiotoxicity; cardiotoxicité; diastolic dysfunction; doxorubicin; doxorubicine; dysfonction diastolique; phosphodiesterase 5; phosphodiestérase 5