Long-acting PDE5 Inhibitor Tadalafil Prevents Early Doxorubicin-induced Left Ventricle Diastolic Dysfunction in Juvenile Mice: Potential Role of Cytoskeletal Proteins

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.