PMID- 19217856
OWN - NLM
STAT- MEDLINE
DCOM- 20090323
LR  - 20220309
IS  - 1542-0086 (Electronic)
IS  - 0006-3495 (Print)
IS  - 0006-3495 (Linking)
VI  - 96
IP  - 4
DP  - 2009 Feb 18
TI  - Doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection 
      by Mito-Q.
PG  - 1388-98
LID - 10.1016/j.bpj.2008.10.042 [doi]
AB  - 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.
FAU - Chandran, Karunakaran
AU  - Chandran K
AD  - Department of Biophysics and Free Radical Research Center, Medical College of 
      Wisconsin, Milwaukee, Wisconsin, USA.
FAU - Aggarwal, Deepika
AU  - Aggarwal D
FAU - Migrino, Raymond Q
AU  - Migrino RQ
FAU - Joseph, Joy
AU  - Joseph J
FAU - McAllister, Donna
AU  - McAllister D
FAU - Konorev, Eugene A
AU  - Konorev EA
FAU - Antholine, William E
AU  - Antholine WE
FAU - Zielonka, Jacek
AU  - Zielonka J
FAU - Srinivasan, Satish
AU  - Srinivasan S
FAU - Avadhani, Narayan G
AU  - Avadhani NG
FAU - Kalyanaraman, B
AU  - Kalyanaraman B
LA  - eng
GR  - R01 CA077822/CA/NCI NIH HHS/United States
GR  - R01 HL073056/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Biophys J
JT  - Biophysical journal
JID - 0370626
RN  - 0 (Cardiotonic Agents)
RN  - 0 (Organophosphorus Compounds)
RN  - 1339-63-5 (Ubiquinone)
RN  - 42VZT0U6YR (Heme)
RN  - 47BYS17IY0 (mitoquinone)
RN  - 80168379AG (Doxorubicin)
RN  - EC 1.9.3.1 (Electron Transport Complex IV)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Body Weight/drug effects
MH  - Cardiomyopathies/chemically induced/*drug therapy/physiopathology
MH  - Cardiotonic Agents/*pharmacology/therapeutic use
MH  - Doxorubicin/*pharmacology/toxicity
MH  - Electron Spin Resonance Spectroscopy
MH  - Electron Transport Complex IV/*metabolism
MH  - Endomyocardial Fibrosis/drug therapy
MH  - Heart/drug effects/physiology
MH  - Heme/physiology
MH  - Male
MH  - Mitochondria, Heart/drug effects/enzymology
MH  - Myocardium/*enzymology
MH  - Organophosphorus Compounds/*pharmacology/therapeutic use
MH  - Random Allocation
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Ubiquinone/*pharmacology/therapeutic use
PMC - PMC2717244
EDAT- 2009/02/17 09:00
MHDA- 2009/03/24 09:00
PMCR- 2010/02/18
CRDT- 2009/02/17 09:00
PHST- 2008/08/11 00:00 [received]
PHST- 2008/10/09 00:00 [accepted]
PHST- 2009/02/17 09:00 [entrez]
PHST- 2009/02/17 09:00 [pubmed]
PHST- 2009/03/24 09:00 [medline]
PHST- 2010/02/18 00:00 [pmc-release]
AID - S0006-3495(08)00128-8 [pii]
AID - BPJ114 [pii]
AID - 10.1016/j.bpj.2008.10.042 [doi]
PST - ppublish
SO  - Biophys J. 2009 Feb 18;96(4):1388-98. doi: 10.1016/j.bpj.2008.10.042.