Oxidative stress and myocardial gene alterations associated with doxorubicin-induced cardiotoxicity in rats persist for two months after treatment cessation

Carole Richard (1) , Steliana Ghibu (2) , Stéphanie Delemasure-Chalumeau (1) , Jean-Claude Guilland (1) , Christine Des Rosiers (3) , Marianne Zeller (1) , Yves Cottin (1) , Luc Rochette (1) , Catherine Vergely (1)

1 LPPCE - Laboratoire de Physiopathologie et de Pharmacologie Cardiovasculaire Expérimentale
2 UMP - University of Medicine and Pharmacy [Cluj-Napoca, Romania]
3 UdeM - Université de Montréal

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.

Domaines: Cardiologie et système cardiovasculaire

Carole Richard, Steliana Ghibu, Stéphanie Delemasure-Chalumeau, Jean-Claude Guilland, Christine Des Rosiers, et al.. Oxidative stress and myocardial gene alterations associated with doxorubicin-induced cardiotoxicity in rats persist for two months after treatment cessation. Journal of Pharmacology and Experimental Therapeutics, 2011, 339 (3), pp.807-814. ⟨10.1124/jpet.111.185892⟩. ⟨hal-03435401⟩