Doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection by Mito-Q.
Doxorubicin (DOX) is used for treating various cancers. Its clinical use is, however, limited by its dose-limiting cardiomyopathy. The exact mechanism of DOX-induced cardiomyopathy still remains unknown. The goals were to investigate the molecular mechanism of DOX-induced cardiomyopathy and cardioprotection by mitoquinone (Mito-Q), a triphenylphosphonium-conjugated analog of coenzyme Q, using a rat model. Rats were treated with DOX, Mito-Q, and DOX plus Mito-Q for 12 weeks. The left ventricular function as measured by two-dimensional echocardiography decreased in DOX-treated rats but was preserved during Mito-Q plus DOX treatment. Using low-temperature ex vivo electron paramagnetic resonance (EPR), a time-dependent decrease in heme signal was detected in heart tissues isolated from rats administered with a cumulative dose of DOX. DOX attenuated the EPR signals characteristic of the exchange interaction between cytochrome c oxidase (CcO)-Fe(III) heme a3 and CuB. DOX and Mito-Q together restored these EPR signals and the CcO activity in heart tissues. DOX strongly downregulated the stable expression of the CcO subunits II and Va and had a slight inhibitory effect on CcO subunit I gene expression. Mito-Q restored CcO subunit II and Va expressions in DOX-treated rats. These results suggest a novel cardioprotection mechanism by Mito-Q during DOX-induced cardiomyopathy involving CcO.
Chandran
Karunakaran
K
Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Aggarwal
Deepika
D
Migrino
Raymond Q
RQ
Joseph
Joy
J
McAllister
Donna
D
Konorev
Eugene A
EA
Antholine
William E
WE
Zielonka
Jacek
J
Srinivasan
Satish
S
Avadhani
Narayan G
NG
Kalyanaraman
B
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D009202:Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004317:Doxorubicin / Q000494:pharmacology* / Q000633:toxicity; D004578:Electron Spin Resonance Spectroscopy; D003576:Electron Transport Complex IV / Q000378:metabolism*; D004719:Endomyocardial Fibrosis / Q000188:drug therapy; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006418:Heme / Q000502:physiology; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology*; D009943:Organophosphorus Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014451:Ubiquinone / Q000494:pharmacology* / Q000627:therapeutic use / Q000031:analogs & derivatives
D002316:Cardiotonic Agents; D009943:Organophosphorus Compounds; D014451:Ubiquinone; D006418:Heme; C429014:mitoquinone; D004317:Doxorubicin; D003576:Electron Transport Complex IV