Abstract 16127: The Pivotal Role of p53 in Doxorubicin-Induced Acute versus Chronic Cardiotoxicity
Introduction: Doxorubicin (DOX) is an effective anticancer chemotherapeutic which also induces acute and chronic cardiotoxicities. Inhibition of p53 activity is cardioprotective against acute cardiotoxicity in adult mice receiving high doses of DOX. However, functional p53 also reduces DOX-induced mitochondrial DNA oxidation. To explain these paradoxical results, we examined the role of p53 in DOX-induced acute and chronic cardiotoxicity with a clinically relevant juvenile mouse model.
Methods: Two week old MHC-CB7 mice (which express dominant-interfering p53 in cardiomyocytes, CMs) 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. CM apoptosis was quantified using anti-active caspase-3 staining. The level of p53, Akt (an anti-apoptotic protein), and ataxia telangiectasia mutated (ATM, a marker for DNA-damage response) was measured by western blot using whole cell and mitochondrial fractions.
Results: During acute stage, left ventricular (LV) systolic function was preserved (Fractional Shortening, FS, 58 ± 2.0% vs. 45 ± 1.3%, p<0.008) and CM apoptosis was reduced (0.003 ± 0.002/mm2 vs. 0.011 ± 0.002/mm2, p<0.008) in MHC-CB7 mice vs. NON-TXG mice. DOX increased mitochondrial p53 and decreased phosphorylated Akt in NON-TXG mice, and increased phosphorylated ATM in MHC-CB7 mice. During late stage, LV systolic function in MHC-CB7 mice markedly deteriorated, reaching values similar to those in NON-TXG mice (FS = 52 ± 2.5% vs. 50 ± 2.0%, p>0.05). CM apoptosis was elevated in MHC-CB7 mice as compared to NON-TXG mice (0.076 ± 0.007 mm2 vs. 0.042 ± 0.008 mm2, p<0.008). Phosphorylated Akt and ATM were normalized during late stage.
Conclusions: Although inhibition of p53 activity protects against DOX-induced CM apoptosis and preserves cardiac function during acute stage, it exacerbates CM apoptosis and cardiac dysfunction during late stage. Ongoing experiments will determine the correlation between mitochondrial DNA damage during acute stage and CM apoptosis during late stage in DOX-treated MHC-CB7 mice.
- © 2011 by American Heart Association, Inc.