Statins Protect Against Early Stages of Doxorubicin-induced Cardiotoxicity Through the Regulation of Akt Signaling and SERCA2
Keith Dadson, Paaladinesh Thavendiranathan, Ludger Hauck, Daniela Grothe, Mohammed Ali Azam, Shanna Stanley-Hasnain, Donya Mahiny-Shahmohammady, Daoyuan Si, Mahmoud Bokhari, Patrick F.H. Lai, Stéphane Massé, Kumaraswamy Nanthakumar, Filio Billia
Abstract
Background: Doxorubicin-induced cardiomyopathy (DICM) is one of the complications that can limit treatment for a significant number of cancer patients. In animal models, the administration of statins can prevent the development of DICM. Therefore, the use of statins with anthracyclines potentially could enable cancer patients to complete their chemotherapy without added cardiotoxicity. The precise mechanism mediating the cardioprotection is not well understood. The purpose of this study is to determine the molecular mechanism by which rosuvastatin confers cardioprotection in a mouse model of DICM. Methods: Rosuvastatin was intraperitoneally administered into adult male mice at 100 μg/kg daily for 7 days, followed by a single intraperitoneal doxorubicin injection at 10 mg/kg. Animals continued to receive rosuvastatin daily for an additional 14 days. Cardiac function was assessed by echocardiography. Optical calcium mapping was performed on retrograde Langendorff perfused isolated hearts. Ventricular tissue samples were analyzed by immunofluorescence microscopy, Western blotting, and quantitative polymerase chain reaction. Results: reuptake. These effects occurred independently of perturbations in ryanodine receptor 2 function. Conclusions: Rosuvastatin counteracts the cardiotoxic effects of doxorubicin by directly targeting sarcoplasmic calcium cycling.