TY - JOUR
T1 - Role of mitochondrial dysfunction in cardiac glycoside toxicity
AU - Liu, Ting
AU - Brown, David A.
AU - O'Rourke, Brian
N1 - Funding Information:
This work was supported by NIH Grants P01 HL081427 and R01 HL101235 (BO'R).
PY - 2010/11
Y1 - 2010/11
N2 - Cardiac glycosides, which inhibit the plasma membrane Na+ pump, are one of the four categories of drug recommended for routine use to treat heart failure, yet their therapeutic window is limited by toxic effects. Elevated cytoplasmic Na+ ([Na+]i) compromises mitochondrial energetics and redox balance by blunting mitochondrial Ca2+ ([Ca2+]m) accumulation, and this impairment can be prevented by enhancing [Ca2+]m. Here, we investigate whether this effect underlies the toxicity and arrhythmogenic effects of cardiac glycosides and if these effects can be prevented by suppressing mitochondrial Ca2+ efflux, via inhibition of the mitochondrial Na+/Ca2+ exchanger (mNCE). In isolated cardiomyocytes, ouabain elevated [Na+]i in a dose-dependent way, blunted [Ca2+]m accumulation, decreased the NADH/NAD+redox potential, and increased reactive oxygen species (ROS). Concomitant treatment with the mNCE inhibitor CGP-37157 ameliorated these effects. CGP-37157 also attenuated ouabain-induced cellular Ca2+ overload and prevented delayed afterdepolarizations (DADs). In isolated perfused hearts, ouabain's positive effects on contractility and respiration were markedly potentiated by CGP-37157, as were those mediated by β-adrenergic stimulation. Furthermore, CGP-37157 inhibited the arrhythmogenic effects of ouabain in both isolated perfused hearts and in vivo. The findings reveal the mechanism behind cardiac glycoside toxicity and show that improving mitochondrial Ca2+ retention by mNCE inhibition can mitigate these effects, particularly with respect to the suppression of Ca2+-triggered arrhythmias, while enhancing positive inotropic actions. These results suggest a novel strategy for the treatment of heart failure.
AB - Cardiac glycosides, which inhibit the plasma membrane Na+ pump, are one of the four categories of drug recommended for routine use to treat heart failure, yet their therapeutic window is limited by toxic effects. Elevated cytoplasmic Na+ ([Na+]i) compromises mitochondrial energetics and redox balance by blunting mitochondrial Ca2+ ([Ca2+]m) accumulation, and this impairment can be prevented by enhancing [Ca2+]m. Here, we investigate whether this effect underlies the toxicity and arrhythmogenic effects of cardiac glycosides and if these effects can be prevented by suppressing mitochondrial Ca2+ efflux, via inhibition of the mitochondrial Na+/Ca2+ exchanger (mNCE). In isolated cardiomyocytes, ouabain elevated [Na+]i in a dose-dependent way, blunted [Ca2+]m accumulation, decreased the NADH/NAD+redox potential, and increased reactive oxygen species (ROS). Concomitant treatment with the mNCE inhibitor CGP-37157 ameliorated these effects. CGP-37157 also attenuated ouabain-induced cellular Ca2+ overload and prevented delayed afterdepolarizations (DADs). In isolated perfused hearts, ouabain's positive effects on contractility and respiration were markedly potentiated by CGP-37157, as were those mediated by β-adrenergic stimulation. Furthermore, CGP-37157 inhibited the arrhythmogenic effects of ouabain in both isolated perfused hearts and in vivo. The findings reveal the mechanism behind cardiac glycoside toxicity and show that improving mitochondrial Ca2+ retention by mNCE inhibition can mitigate these effects, particularly with respect to the suppression of Ca2+-triggered arrhythmias, while enhancing positive inotropic actions. These results suggest a novel strategy for the treatment of heart failure.
KW - Arrhythmias
KW - Cardiac glycosides
KW - Energy metabolism
KW - Heart failure
KW - Ion transport
KW - Na/Ca exchanger
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U2 - 10.1016/j.yjmcc.2010.06.012
DO - 10.1016/j.yjmcc.2010.06.012
M3 - Article
C2 - 20620145
AN - SCOPUS:77957242874
SN - 0022-2828
VL - 49
SP - 728
EP - 736
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 5
ER -