P21 WAF1/Cip1/Sdi1 knockout mice respond to doxorubicin with reduced cardiotoxicity

Jerome Terrand, Beibei Xu, Steve Morrissy, Thai Nho Dinh, Stuart Williams, Qin M. Chen

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)102-110
Number of pages9
JournalToxicology and Applied Pharmacology
Volume257
Issue number1
DOIs
StatePublished - Nov 15 2011

Keywords

  • Antioxidant enzymes
  • Cardiomyopathy
  • Cell cycle inhibitor
  • Inflammatory response

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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