Abstract 16959: Cardiomyocyte-Restricted Inhibition of p53 Activity Exacerbates Late Stage Doxorubicin Cardiotoxicity in a Juvenile Mouse Model
Introduction: Doxorubicin (DOX) is an effective anti-cancer therapeutic which induces transient cardiotoxicy during acute drug delivery. Cardiotoxicity re-occurs in some patients years after drug treatment is terminated. Previous studies demonstrated administration of high doses of DOX to adult mice induces rapid cardiomyocyte (CM) atrophy and concomitant cardiac dysfunction via p53-dependent inhibition of mammalian target of rapamycin activity. Here, we examined the role p53 inhibition in a more clinically relevant model of DOX cardiotoxicity.
Methods: Juvenile MHC-CB7 mice (which express dominant-interfering p53 in CMs) and their non-transgenic (NON-TXG) littermates were given weekly DOX injections for a total of 5 weeks (25 mg/kg cumulative dose). Animals were studied 1 week (acute stage) or 13 weeks (late stage) after the last DOX injection. Cardiac function was measured with 2D echocardiography. CM apoptosis was quantified using anti-active caspase-3 staining. CM atrophy was quantified with minimal fiber diameter (MFD) measurement.
Results: Left ventricular systolic function was preserved (Fractional Shortening, FS, 58 ± 2.0% vs. 45 ± 1.3%, p<0.008), the prevalence of CM apoptosis was reduced (0.003 ± 0.002/mm2 vs. 0.011 ± 0.002/mm2, p<0.008), and CM MFD was preserved (11.72 ± 0.38μm vs. 9.70 ± 0.40μm, p<0.008) in DOX-treated MHC-CB7 mice as compared to DOX-treated NON-TXG mice. In contrast, inhibition of p53 activity was no longer cardioprotective during late stage disease. The systolic function in DOX-treated MHC-CB7 mice markedly deteriorated, reaching values similar to those in DOX-treated NON-TXG mice (FS = 52 ± 2.5% vs. 50 ± 2.0%, p>0.05). Surprisingly, late stage CM apoptosis was elevated in DOX-treated MHC-CB7 mice as compared to DOX-treated NON-TXG mice (0.076 ± 0.007 mm2 vs. 0.042 ± 0.008 mm2, p<0.008). Late stage cardiotoxicity was not associated with CM atrophy as indicated by CM MFD (12.32 ± 0.26μm vs. 12.24 ± 0.35μm in DOX-treated MHC-CB7 mice vs. DOX-treated NON-TXG mice, p>0.05).
Conclusions: These data indicate that p53 inhibition attenuates acute stage cardiotoxicity but exacerbates late stage DOX cardiotoxicity, suggesting that there are differential underlying mechanisms for acute vs. late disease.
- © 2010 by American Heart Association, Inc.