Faculty Collaboration Database

Doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection by Mito-Q. Biophys J 2009 Feb 18;96(4):1388-98

Date

02/17/2009

Pubmed ID

19217856

Pubmed Central ID

PMC2717244

DOI

10.1016/j.bpj.2008.10.042

Scopus ID

2-s2.0-62649160560 (requires institutional sign-in at Scopus site)   159 Citations

Abstract

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.

Author List

Chandran K, Aggarwal D, Migrino RQ, Joseph J, McAllister D, Konorev EA, Antholine WE, Zielonka J, Srinivasan S, Avadhani NG, Kalyanaraman B

Authors

Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin
Jacek M. Zielonka PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Body Weight
Cardiomyopathies
Cardiotonic Agents
Doxorubicin
Electron Spin Resonance Spectroscopy
Electron Transport Complex IV
Endomyocardial Fibrosis
Heart
Heme
Male
Mitochondria, Heart
Myocardium
Organophosphorus Compounds
Random Allocation
Rats
Rats, Sprague-Dawley
Ubiquinone