title: p21(WAF1/Cip1/Sdi1) knockout mice respond to doxorubicin with reduced cardiotoxicity.
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.
authors.affiliation: Department of Pharmacology,College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ 85724, USA.
authors.forename: Jerome
authors.initials: J
authors.lastname: Terrand
authors.forename: Beibei
authors.initials: B
authors.lastname: Xu
authors.forename: Steve
authors.initials: S
authors.lastname: Morrissy
authors.forename: Thai Nho
authors.initials: TN
authors.lastname: Dinh
authors.forename: Stuart
authors.initials: S
authors.lastname: Williams
authors.forename: Qin M
authors.initials: QM
authors.lastname: Chen
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D009202:Cardiomyopathies / Q000139:chemically induced*; D002374:Catalase / Q000096:biosynthesis / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000502:physiology; D004317:Doxorubicin / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects; D005434:Flow Cytometry; D005979:Glutathione Peroxidase / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004317:Doxorubicin; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase