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Doxorubicin-induced cardiac dysfunction is attenuated by cyclosporine treatment in mice through improvements in mitochondrial bioenergetics

Abstract : We tested whether inhibition of mitochondrial membrane potential dissipation by cyclosporine A would prevent doxorubicin-induced myocardial and mitochondrial dysfunction. Acute and sub-chronic models of doxorubicin exposition were performed in mice with either a single intra peritoneal bolus (10 mg/kg, i.p.) or one injection of 4 mg/kg per week during five weeks. Follow-up was 1.5 week and 16 weeks in acute and sub-chronic models, respectively. Mice received either cyclosporine A (1mg/kg i.p. on alternate days) or saline until follow-up. Heart function was evaluated by echocardiography. Mitochondrial measurements included oxygen consumption, membrane potential and externally added calcium-induced mitochondrial permeability transition. Mitochondrial mass was evaluated by transmission electronic microscopy and mitochondrial DNA content. Mitochondrial dynamics was detected as the expression of GTPases involved in mitochondrial fusion and fission. In both acute and chronic models, doxorubicin decreased left ventricular fractional shortening and survival. Heart function and survival were improved by cyclosporine A, but not by tacrolimus (FK506), a cyclosporine derivative with no inhibitory effect on mitochondrial transition pore. In the acute model, doxorubicin exposure was associated with increased mitochondrial DNA content, mitochondrial fragmentation and changes in mitochondrial fusion and fission-related transcripts (increases in Mfn2, OPA1, Fis1, and no changes in Drp1). Cyclosporine A did not alter mitochondrial biogenesis, but prevented mitochondrial fragmentation and partially restored mitochondrial energy-producing capacity. These findings suggest that in vivo cyclosporine A treatment may limit mitochondrial permeability transition pore opening, mitochondrial potential loss and contractile depression in acute and chronic models of cardiac toxicity induced by doxorubicin.
keyword : Medicine
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https://hal.archives-ouvertes.fr/hal-00717079
Contributor : Hal Peer <>
Submitted on : Thursday, July 12, 2012 - 2:56:06 AM
Last modification on : Friday, April 10, 2020 - 3:14:04 PM
Long-term archiving on: : Thursday, December 15, 2016 - 10:03:36 PM

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Xavier Marechal, David Montaigne, Camille Marciniak, Philippe Marchetti, Sidi Mohamed Hassoun, et al.. Doxorubicin-induced cardiac dysfunction is attenuated by cyclosporine treatment in mice through improvements in mitochondrial bioenergetics. Clinical Science, Portland Press, 2011, 121 (9), pp.405-413. ⟨10.1042/CS20110069⟩. ⟨hal-00717079⟩

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