title: Sexual dimorphism of doxorubicin-mediated cardiotoxicity: potential role of energy metabolism remodeling.
abstract: BACKGROUND
  Cardiovascular diseases are the major cause of mortality among both men and women with a lower incidence in women before menopause. The clinical use of doxorubicin, widely used as an antineoplastic agent, is markedly hampered by severe cardiotoxicity. Even if there is a significant sex difference in incidence of cardiovascular disease at the adult stage, it is not known whether a difference in doxorubicin-related cardiotoxicity between men and women also exists. The objective of this work was to explore the cardiac side effects of doxorubicin in adult rats and decipher whether signaling pathways involved in cardiac toxicity differ between sexes.
  
  
  RESULTS
  After 7 weeks of doxorubicin (2 mg/kg per week), males developed major signs of cardiomyopathy with cardiac atrophy, reduced left ventricular ejection fraction and 50% mortality. In contrast, no female died and their left ventricular ejection fraction was only moderately affected. Surprisingly, neither global oxidation levels nor the antioxidant response nor the apoptosis signaling pathways were altered by doxorubicin. However, the level of total adenosine monophosphate-activated protein kinase was severely decreased only in males. Moreover, markers of mitochondrial biogenesis and cardiolipin content were strongly reduced only in males. To analyze the onset of the pathology, maximal oxygen consumption rate of left ventricular permeabilized fibers after 4 weeks of treatment was reduced only in doxorubicin-treated males.
  
  
  CONCLUSIONS
  Altogether, these results clearly evidence sex differences in doxorubicin toxicity. Cardiac mitochondrial dysfunction and adenosine monophosphate-activated protein kinase seem as critical sites of sex differences in cardiotoxicity as evidenced by significant statistical interactions between sex and treatment effects.
authors.affiliation: From the INSERM UMR-S 769, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., M.G., F.L., M.G., V.V., A.G., R.V.-C.); IPSIT-IFR141 Université de Paris-Sud, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., C.R.-M., M.G., F.L., M.G., A.S., V.V., A.G., R.V.-C.); INSERM UMR-S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France (C.R.-M.); and IPSIT-IFR141 Service d'Analyse des Médicaments et Métabolites, Châtenay-Malabry, France (A.S.). maryline.moulin@u-psud.fr.
authors.forename: Maryline
authors.initials: M
authors.lastname: Moulin
authors.affiliation: From the INSERM UMR-S 769, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., M.G., F.L., M.G., V.V., A.G., R.V.-C.); IPSIT-IFR141 Université de Paris-Sud, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., C.R.-M., M.G., F.L., M.G., A.S., V.V., A.G., R.V.-C.); INSERM UMR-S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France (C.R.-M.); and IPSIT-IFR141 Service d'Analyse des Médicaments et Métabolites, Châtenay-Malabry, France (A.S.).
authors.forename: Jérôme
authors.initials: J
authors.lastname: Piquereau
authors.affiliation: From the INSERM UMR-S 769, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., M.G., F.L., M.G., V.V., A.G., R.V.-C.); IPSIT-IFR141 Université de Paris-Sud, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., C.R.-M., M.G., F.L., M.G., A.S., V.V., A.G., R.V.-C.); INSERM UMR-S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France (C.R.-M.); and IPSIT-IFR141 Service d'Analyse des Médicaments et Métabolites, Châtenay-Malabry, France (A.S.).
authors.forename: Philippe
authors.initials: P
authors.lastname: Mateo
authors.affiliation: From the INSERM UMR-S 769, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., M.G., F.L., M.G., V.V., A.G., R.V.-C.); IPSIT-IFR141 Université de Paris-Sud, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., C.R.-M., M.G., F.L., M.G., A.S., V.V., A.G., R.V.-C.); INSERM UMR-S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France (C.R.-M.); and IPSIT-IFR141 Service d'Analyse des Médicaments et Métabolites, Châtenay-Malabry, France (A.S.).
authors.forename: Dominique
authors.initials: D
authors.lastname: Fortin
authors.affiliation: From the INSERM UMR-S 769, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., M.G., F.L., M.G., V.V., A.G., R.V.-C.); IPSIT-IFR141 Université de Paris-Sud, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., C.R.-M., M.G., F.L., M.G., A.S., V.V., A.G., R.V.-C.); INSERM UMR-S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France (C.R.-M.); and IPSIT-IFR141 Service d'Analyse des Médicaments et Métabolites, Châtenay-Malabry, France (A.S.).
authors.forename: Catherine
authors.initials: C
authors.lastname: Rucker-Martin
authors.affiliation: From the INSERM UMR-S 769, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., M.G., F.L., M.G., V.V., A.G., R.V.-C.); IPSIT-IFR141 Université de Paris-Sud, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., C.R.-M., M.G., F.L., M.G., A.S., V.V., A.G., R.V.-C.); INSERM UMR-S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France (C.R.-M.); and IPSIT-IFR141 Service d'Analyse des Médicaments et Métabolites, Châtenay-Malabry, France (A.S.).
authors.forename: Mélanie
authors.initials: M
authors.lastname: Gressette
authors.affiliation: From the INSERM UMR-S 769, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., M.G., F.L., M.G., V.V., A.G., R.V.-C.); IPSIT-IFR141 Université de Paris-Sud, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., C.R.-M., M.G., F.L., M.G., A.S., V.V., A.G., R.V.-C.); INSERM UMR-S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France (C.R.-M.); and IPSIT-IFR141 Service d'Analyse des Médicaments et Métabolites, Châtenay-Malabry, France (A.S.).
authors.forename: Florence
authors.initials: F
authors.lastname: Lefebvre
authors.affiliation: From the INSERM UMR-S 769, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., M.G., F.L., M.G., V.V., A.G., R.V.-C.); IPSIT-IFR141 Université de Paris-Sud, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., C.R.-M., M.G., F.L., M.G., A.S., V.V., A.G., R.V.-C.); INSERM UMR-S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France (C.R.-M.); and IPSIT-IFR141 Service d'Analyse des Médicaments et Métabolites, Châtenay-Malabry, France (A.S.).
authors.forename: Milada
authors.initials: M
authors.lastname: Gresikova
authors.affiliation: From the INSERM UMR-S 769, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., M.G., F.L., M.G., V.V., A.G., R.V.-C.); IPSIT-IFR141 Université de Paris-Sud, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., C.R.-M., M.G., F.L., M.G., A.S., V.V., A.G., R.V.-C.); INSERM UMR-S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France (C.R.-M.); and IPSIT-IFR141 Service d'Analyse des Médicaments et Métabolites, Châtenay-Malabry, France (A.S.).
authors.forename: Audrey
authors.initials: A
authors.lastname: Solgadi
authors.affiliation: From the INSERM UMR-S 769, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., M.G., F.L., M.G., V.V., A.G., R.V.-C.); IPSIT-IFR141 Université de Paris-Sud, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., C.R.-M., M.G., F.L., M.G., A.S., V.V., A.G., R.V.-C.); INSERM UMR-S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France (C.R.-M.); and IPSIT-IFR141 Service d'Analyse des Médicaments et Métabolites, Châtenay-Malabry, France (A.S.).
authors.forename: Vladimir
authors.initials: V
authors.lastname: Veksler
authors.affiliation: From the INSERM UMR-S 769, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., M.G., F.L., M.G., V.V., A.G., R.V.-C.); IPSIT-IFR141 Université de Paris-Sud, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., C.R.-M., M.G., F.L., M.G., A.S., V.V., A.G., R.V.-C.); INSERM UMR-S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France (C.R.-M.); and IPSIT-IFR141 Service d'Analyse des Médicaments et Métabolites, Châtenay-Malabry, France (A.S.).
authors.forename: Anne
authors.initials: A
authors.lastname: Garnier
authors.affiliation: From the INSERM UMR-S 769, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., M.G., F.L., M.G., V.V., A.G., R.V.-C.); IPSIT-IFR141 Université de Paris-Sud, Châtenay-Malabry, France (M.M., J.P., P.M., D.F., C.R.-M., M.G., F.L., M.G., A.S., V.V., A.G., R.V.-C.); INSERM UMR-S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France (C.R.-M.); and IPSIT-IFR141 Service d'Analyse des Médicaments et Métabolites, Châtenay-Malabry, France (A.S.).
authors.forename: Renée
authors.initials: R
authors.lastname: Ventura-Clapier
mesh_terms: D000818:Animals; D015992:Body Mass Index; D066126:Cardiotoxicity; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity*; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012737:Sex Factors; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D004317:Doxorubicin
keywords: AMP-activated protein kinase; PGC-1alpha protein; anthracyclines; heart failure; mitochondria; sex differences