Cyclin D2‐mediated cardiomyocyte cell cycle activity reverses doxorubicin‐induced cardiotoxicity

Abstract

Doxorubicin (DOX) is an effective anticancer agent which also induces acute and chronic cardiotoxicities. We hypothesize that activation of cardiomyocyte (CM) cell cycle protects against DOX‐induced cardiotoxicity. Two week old MHC‐cyclin D2 (D2) mice and their non‐transgenic (NON‐TXG) littermates were given weekly DOX injections for 5 weeks (25 mg/kg total dose). Animals were studied 1 week (acute stage) or 13 weeks (late stage) after the last DOX injection. Cardiac function was measured with echocardiography and CM cell cycle was quantified using a tritiated thymidine incorporation assay. Our results showed that CM cell cycle was increased in D2 mice as compared to NON‐TXG mice (thymidine positive CM nuclei, 0.03±0.01% vs. 0.002±0.002 in acute stage, p<0.01; and 0.03±0.01% vs. 0.001±0.001 in late stage, p<0.01). In the absence of cell cycle activity, cardiac function remained depressed in late stage vs. acute stage (Fractional Shortening, FS, 41.4±3.1% vs. 44.0±3.2%, p>;0.05), whereas in the presence of CM cell cycle activity, cardiac function improved in late stage vs. acute stage (FS = 60.1±1.3% vs. 47.1±3.3%, p<0.01). CM apoptosis (0.02±0.01/mm2 vs. 0.05±0.01/mm2, p<0.01) and fibrosis (6.2±0.9% vs. 12.0±1.7%, p<0.01) was reduced in D2 mice as compared to NON‐TXG mice in late stage. For the first time, our data suggest activation of CM cell cycle in adult mice reverses DOX‐induced cardiotoxicity.