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Updated: May 29, 2026
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
p21(WAF1/Cip1/Sdi1) knockout mice respond to doxorubicin with reduced cardiotoxicity
Jerome Terrand1, Beibei Xu, Steve Morrissy
1Department of Pharmacology,College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ 85724, USA.
Abstract:
Doxorubicin (Dox) is an antineoplastic agent that can cause cardiomyopathy in humans and experimental animals. As an inducer of reactive oxygen species and a DNA damaging agent, Dox causes elevated expression of p21(WAF1/Cip1/Sdi1) (p21) gene. Elevated levels of p21 mRNA and p21 protein have been detected in the myocardium of mice following Dox treatment. With chronic treatment of Dox, wild type (WT) animals develop cardiomyopathy evidenced by elongated nuclei, mitochondrial swelling, myofilamental disarray, reduced cardiac output, reduced ejection fraction, reduced left ventricular contractility, and elevated expression of ANF gene. In contrast, p21 knockout (p21KO) mice did not show significant changes in the same parameters in response to Dox treatment. In an effort to understand the mechanism of the resistance against Dox induced cardiomyopathy, we measured levels of antioxidant enzymes and found that p21KO mice did not contain elevated basal or inducible levels of glutathione peroxidase and catalase. Measurements of 6 circulating cytokines indicated elevation of IL-6, IL-12, IFNγ and TNFα in Dox treated WT mice but not p21KO mice. Dox induced elevation of IL-6 mRNA was detected in the myocardium of WT mice but not p21KO mice. While the mechanism of the resistance against Dox induced cardiomyopathy remains unclear, lack of inflammatory response may contribute to the observed cardiac protection in p21KO mice.
Insights
Mice lacking the p21 gene resist doxorubicin-induced cardiomyopathy. This protection may stem from a reduced inflammatory response, highlighting p21
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Toxicology
Background:
- Doxorubicin (Dox) is a potent antineoplastic agent with known cardiotoxic effects.
- Doxorubicin induces reactive oxygen species and DNA damage, leading to elevated p21 gene expression.
- Wild-type (WT) mice develop cardiomyopathy after Dox treatment, characterized by structural and functional cardiac changes.
Purpose of the Study:
- To investigate the protective mechanism against Dox-induced cardiomyopathy in p21 knockout (p21KO) mice.
- To compare the cardiac response to Dox in WT and p21KO mice.
- To explore the role of antioxidant enzymes and inflammatory cytokines in Dox cardiotoxicity.
Main Methods:
- Chronic Doxorubicin administration to WT and p21KO mice.
- Assessment of cardiac function (cardiac output, ejection fraction, contractility) and histology.
- Measurement of antioxidant enzyme levels (glutathione peroxidase, catalase).
- Quantification of circulating cytokines (IL-6, IL-12, IFNγ, TNFα) and cardiac IL-6 mRNA.
Main Results:
- p21KO mice exhibited resistance to Dox-induced cardiomyopathy, showing no significant cardiac dysfunction or structural damage.
- Unlike WT mice, p21KO mice did not display elevated levels of antioxidant enzymes or inflammatory cytokines following Dox treatment.
- Dox-induced elevation of IL-6 mRNA was observed in the myocardium of WT mice but not in p21KO mice.
Conclusions:
- The absence of the p21 gene confers significant protection against Dox-induced cardiotoxicity.
- Reduced inflammatory response, indicated by lower cytokine levels, likely contributes to cardiac protection in p21KO mice.
- Further research is needed to fully elucidate the resistance mechanisms against Dox-induced cardiomyopathy.
