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Sexual dimorphism of doxorubicin-mediated cardiotoxicity: potential role of energy metabolism remodeling.
Moulin, Maryline; Piquereau, Jérôme; Mateo, Philippe; Fortin, Dominique; Rucker-Martin, Catherine; Gressette, Mélanie; Lefebvre, Florence; Gresikova, Milada; Solgadi, Audrey; Veksler, Vladimir; Garnier, Anne; Ventura-Clapier, Renée.
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  • Moulin M; 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 Lannelon
  • Piquereau J; 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 Lannelon
  • Mateo P; 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 Lannelon
  • Fortin D; 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 Lannelon
  • Rucker-Martin C; 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 Lannelon
  • Gressette M; 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 Lannelon
  • Lefebvre F; 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 Lannelon
  • Gresikova M; 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 Lannelon
  • Solgadi A; 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 Lannelon
  • Veksler V; 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 Lannelon
  • Garnier A; 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 Lannelon
  • Ventura-Clapier R; 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 Lannelon
Circ Heart Fail ; 8(1): 98-108, 2015 Jan.
Article en En | MEDLINE | ID: mdl-25420486
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. METHODS AND 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Doxorrubicina / Función Ventricular Izquierda / Metabolismo Energético / Insuficiencia Cardíaca Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Circ Heart Fail Asunto de la revista: ANGIOLOGIA / CARDIOLOGIA Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Doxorrubicina / Función Ventricular Izquierda / Metabolismo Energético / Insuficiencia Cardíaca Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Circ Heart Fail Asunto de la revista: ANGIOLOGIA / CARDIOLOGIA Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos