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

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.

journal_name

J Mol Cell Cardiol

journal_title

Journal of molecular and cellular cardiology

authors

Solem LE,Heller LJ,Wallace KB

doi

10.1006/jmcc.1996.0095

subject

Has Abstract

pub_date

1996-05-01 00:00:00

pages

1023-32

issue

5

eissn

0022-2828

issn

1095-8584

pii

S0022-2828(96)90095-4

journal_volume

28

pub_type

杂志文章

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