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The pivotal role of p53 in doxorubicin‐induced acute versus chronic cardiotoxicity
Author(s) -
Zhu Wuqiang,
Reuter Sean,
Wagner Gregory R,
Payne Ronald M,
Field Loren J
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.528.2
Subject(s) - apoptosis , cardiotoxicity , doxorubicin , cardiac function curve , medicine , stage (stratigraphy) , endocrinology , heart failure , chemotherapy , chemistry , biology , paleontology , biochemistry
We examined the role of p53 in doxorubicin (DOX)‐induced acute and chronic cardiotoxicities with a clinically relevant juvenile mouse model. 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 last DOX injection. Cardiac function was measured with echocardiography. CM apoptosis was quantified using immunohistology. During acute stage, cardiac function was preserved (Fractional Shortening, FS, 58±2.0% vs. 45±1.3%, p<0.01) and CM apoptosis was reduced (0.003±0.002/mm2 vs. 0.011±0.002/mm2, p<0.01) in CB7 mice vs. NON‐TXG mice. During late stage, cardiac function in 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 CB7 mice as compared to NON‐TXG mice (0.076±0.007 mm2 vs. 0.042±0.008 mm2, p<0.01). In conclusion, 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. We are determining the correlation between mitochondrial DNA damage during acute stage and CM apoptosis during late stage. Grant Funding Source : NIH, American Cancer Society