Doxorubicin Inactivates Myocardial Cytochrome c Oxidase in Rats: Cardioprotection by Mito-Q

被引：147

作者：

Chandran, Karunakaran ^{[1
,2
]}

Aggarwal, Deepika ^{[3
]}

Migrino, Raymond Q. ^{[4
]}

Joseph, Joy ^{[1
,2
]}

McAllister, Donna ^{[1
,2
]}

Konorev, Eugene A. ^{[5
]}

Antholine, William E. ^{[1
,2
]}

Zielonka, Jacek ^{[1
,2
]}

Srinivasan, Satish ^{[6
]}

Avadhani, Narayan G. ^{[6
]}

Kalyanaraman, B. ^{[1
,2
]}

机构：

[1] Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA

[2] Med Coll Wisconsin, Free Rad Res Ctr, Milwaukee, WI 53226 USA

[3] Dr Reddys Labs, Hyderabad, Andhra Pradesh, India

[4] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA

[5] Univ Hawaii, Coll Pharm, Dept Pharmaceut Sci, Hilo, HI 96720 USA

[6] Univ Penn, Sch Vet Med, Dept Anim Biol, Philadelphia, PA 19104 USA

来源：

BIOPHYSICAL JOURNAL | 2009年 / 96卷 / 04期

关键词：

ELECTRON-PARAMAGNETIC-RESONANCE; BREAST-CANCER PATIENTS; REACTIVE OXYGEN; NITRIC-OXIDE; ANTHRACYCLINE CARDIOTOXICITY; GLUTATHIONE-PEROXIDASE; SUPEROXIDE-DISMUTASE; ENDOTHELIAL-CELLS; RESPIRATORY-CHAIN; INDUCED APOPTOSIS;

D O I：

10.1016/j.bpj.2008.10.042

中图分类号：

Q6 [生物物理学];

学科分类号：

071011 ;

摘要：

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 cardionnyopathy 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 a(3) and Cu-B. DOX and Mito-Q together restored these EPR signals and the CcO activity in heart tissues. DOX strongly clownregulated 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-O during DOX-induced cardiomyopathy involving CcO.

引用

页码：1388 / 1398

页数：11

共 57 条

[1] Redox reactions of the iron-sulfur cluster in a ribosomal RNA methyltransferase, RumA - Optical and EPR studies
Agarwalla, S
Stroud, RM
Gaffney, BJ
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (33) : 34123 - 34129
[2] Fine-tuning the hydrophobicity of a mitochondria-targeted antioxidant
Asin-Cayuela, J
Manas, ARB
James, AM
Smith, RAJ
Murphy, MP
[J]. FEBS LETTERS, 2004, 571 (1-3): : 9 - 16
[3] BRISTOW MR, 1978, CANCER TREAT REP, V62, P873
[4] The nature of the exchange coupling between high-spin Fe(III) herne o3 and CuB(II) in Escherichia coli quinol oxidase, cytochrome bo3:: MCD and EPR studies
Cheesman, MR
Oganesyan, VS
Watmough, NJ
Butler, CS
Thomson, AJ
[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2004, 126 (13) : 4157 - 4166
[5] Conklin Kenneth A, 2005, Integr Cancer Ther, V4, P110, DOI 10.1177/1534735405276191
[6] COOPER CE, 1992, J BIOL CHEM, V267, P280
[7] DAVIES KJA, 1986, J BIOL CHEM, V261, P3060
[8] Mitochondria superoxide dismutase mimetic inhibits peroxide-induced oxidative damage and apoptosis: Role of mitochondrial superoxide
Dhanasekaran, A
Kotamraju, S
Karunakaran, C
Kalivendi, SV
Thomas, S
Joseph, J
Kalyanaraman, B
[J]. FREE RADICAL BIOLOGY AND MEDICINE, 2005, 39 (05) : 567 - 583
[9] Dorr RT, 1996, SEMIN ONCOL, V23, P23
[10] Chemotherapy and cardiotoxicity in older breast cancer patients: A population-based study
Doyle, JJ
Neugut, AI
Jacobson, JS
Grann, VR
Hershman, DL
[J]. JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (34) : 8597 - 8605

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