PT - JOURNAL ARTICLE AU - Carole Richard AU - Steliana Ghibu AU - Stéphanie Delemasure-Chalumeau AU - Jean-Claude Guilland AU - Christine Des Rosiers AU - Marianne Zeller AU - Yves Cottin AU - Luc Rochette AU - Catherine Vergely TI - Oxidative Stress and Myocardial Gene Alterations Associated with Doxorubicin-Induced Cardiotoxicity in Rats Persist for 2 Months after Treatment Cessation AID - 10.1124/jpet.111.185892 DP - 2011 Dec 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 807--814 VI - 339 IP - 3 4099 - http://jpet.aspetjournals.org/content/339/3/807.short 4100 - http://jpet.aspetjournals.org/content/339/3/807.full SO - J Pharmacol Exp Ther2011 Dec 01; 339 AB - The molecular mechanisms underlying doxorubicin (DOX)-induced cardiomyopathy include alterations in cardiomyocytes' oxidative stress status and in gene expression. Although such alterations have been reported during in vivo DOX treatment of animals, it remains to be clarified whether they persist after treatment cessation. To address this question, rats were injected with either saline (1 ml/kg/day i.p; control) or DOX (1 mg/kg/day i.p.) for 10 days, and 70 days later cardiac functional parameters were evaluated in vivo by left ventricular catheterization. Hearts were also harvested for histological analyses as well as measurements of oxidative stress parameters by various techniques and gene expression by quantitative polymerase chain reaction of markers of cardiac pathological remodeling, namely atrial natriuretic factor, myosin heavy chain β, vascular endothelial growth factor A (VEGF-A), and sarcoplasmic reticulum Ca+2 ATPase. Compared with controls, DOX-treated rats displayed marked alterations in most parameters even 2 months after cessation of treatment. These included 1) lower left ventricular contractility (+dP/dt), 2) increased levels of plasma and myocardial oxidative stress markers, namely thiobarbituric acid reactive substances or dihydroethidium fluorescence, and 3) markedly altered transcript levels for all measured markers of cardiac remodeling, except VEGF-A. These changes correlated significantly with +dP/dt values assessed in the two groups of animals. In conclusion, this study demonstrated that as many as 2 months after cessation of DOX treatment cardiac alterations persisted, reflecting increased oxidative stress and pathological remodeling, the latter being linked to the development of contractile dysfunction.