Dose-dependent increase in sensitivity to calcium-induced mitochondrial dysfunction and cardiomyocyte cell injury by doxorubicin

L. E. Solem, L. J. Heller, K. B. Wallace, Kendall B Wallace

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83 Scopus citations

Abstract

We previously reported the induction of calcium-dependent calcium release and depolarization of membrane potential of cardiac mitochondria from rats treated chronically (13 weeks) with doxorubicin. The fact that this was inhibited by cyclosporine A and ruthenium red suggests induction of the mitochondrial permeability transition and calcium cycling. The objective of this investigation was to characterize the cumulative dose-dependent interference with mitochondrial calcium transport by doxorubicin and to assess whether alteration of mitochondrial calcium regulation is manifested as an increased sensitivity to calcium-induced injury to cardiomyocytes isolated from rats exposed in vivo. Mitochondria or cardiomyocytes were isolated from rats treated with 2 mg/kg/week doxorubicin s.c. for 1-9 weeks. Mitochondria isolated from hearts of doxorubicin-treated rats exhibited a dose-dependent increase in sensitivity to calcium-induced calcium release and membrane depolarization, both of which were inhibited by cyclosporine A. Cardiomyocytes isolated from rats treated for 6 weeks with doxorubicin expressed an increased sensitivity to calcium-induced cell killing. The calcium intolerance was prevented by adding either cyclosporine A or ruthenium red to block mitochondrial calcium cycling. These data demonstrate that doxorubicin treatment in vivo causes: (1) a dose-dependent interference with mitochondrial calcium transport and calcium-dependent regulation of membrane potential indicative of induction of the mitochondrial permeability transition, and (2) an increased sensitivity to calcium-induced loss of cell viability. The fact that blocking mitochondrial calcium cycling protected cardiomyocytes from the calcium intolerance suggests that altered regulation of mitochondrial calcium transport may be a critical event in doxorubicin-induced cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)1023-1032
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume28
Issue number5
DOIs
StatePublished - May 1996

Keywords

  • Adriamycin
  • Calcium
  • Cardiac
  • Doxorubicin
  • Mitochondria
  • Mitochondrial permeability transition

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