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Doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection by Mito-Q.

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.

SUBMITTER: Chandran K

PROVIDER: S-EPMC2717244 | biostudies-other | 2009 Feb

REPOSITORIES: biostudies-other

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Doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection by Mito-Q.

Chandran Karunakaran K 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

Biophysical journal 20090201 4

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 ...[more]

PMID: 19217856

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Project description:BACKGROUND:Treatment of heart failure remains one of the most challenging task for intensive care medicine, cardiology and cardiac surgery. New options and better indicators are always required. Understanding the basic mechanisms underlying heart failure promote the development of adjusted therapy e.g. assist devices and monitoring of recovery. If cardiac failure is related to compromised cellular respiration of the heart, remains unclear. Myocardial respiration depends on Cytochrome c- Oxidase (CytOx) activity representing the rate limiting step for the mitochondrial respiratory chain. The enzymatic activity as well as mRNA expression of enzyme's mitochondrial encoded catalytic subunit 2, nuclear encoded regulatory subunit 4 and protein contents were studied in biopsies of cardiac patients suffering from myocardial insufficiency and dilated cardiomyopathy (DCM). METHODS:Fifty-four patients were enrolled in the study and underwent coronary angiography. Thirty male patients (mean age: 45 +/-?15 yrs.) had a reduced ejection fraction (EF) 35?±?12% below 45% and a left ventricular end diastolic diameter (LVEDD) of 71?±?10 mm bigger than 56 mm. They were diagnosed as having idiopathic dilated cardiomyopathy (DCM) without coronary heart disease and NYHA-class 3 and 4. Additionally, 24 male patients (mean age: 52 +/-?11 yrs.) after exclusion of secondary cardiomyopathies, coronary artery or valve disease, served as control (EF: 68?±?7, LVEDD: 51?±?7 mm). Total RNA was extracted from two biopsies of each person. Real-time PCR analysis was performed with specific primers followed by a melt curve analysis. Corresponding protein expression in the tissue was studied with immune-histochemistry while enzymatic activity was evaluated by spectroscopy. RESULTS:Gene and protein expression analysis of patients showed a significant decrease of subunit 4 (1.1 vs. 0.6, p?<?0.001; 7.7?±?3.1% vs. 2.8?±?1.4%, p?<?0.0001) but no differences in subunit 2. Correlations were found between reduced subunit 2 expression, low EF (r?=?0.766, p?<?0.00045) and increased LVEDD (r?=?0.492, p?<?0.0068). In case of DCM less subunit 4 expression and reduced shortening fraction (r?=?0.524, p?<?0.017) was found, but enzymatic activity was higher (0.08?±?0.06 vs. 0.26?±?0.08 U/mg, p?<?0.001) although myocardial oxygen consumption continued to the same extent. CONCLUSION:In case of myocardial insufficiency and DCM, decreased expression of COX 4 results in an impaired CytOx activity. Higher enzymatic activity but equal oxygen consumption contribute to the pathophysiology of the myocardial insufficiency and appears as an indicator of oxidative stress. This kind of dysregulation should be in the focus for the development of diagnostic and therapy procedures.

Project description:BackgroundMetabonomics is a useful tool for studying mechanisms of drug treatment using systematic metabolite profiles. Ginsenosides Rg1 and Rb1, ophiopogonin D, and schizandrin are the main bioactive components of a traditional Chinese formula (Sheng-Mai San) widely used for the treatment of coronary heart disease. It remains unknown the effect of individual bioactive component and how the multi-components in combination affect the treating acute myocardial infarction (AMI).MethodsRats were divided into 7 groups and dosed consecutively for 7 days with mono and combined-therapy administrations. Serum samples were analyzed by proton nuclear magnetic resonance (1H NMR) spectroscopy. Partial least squares discriminate analysis (PLS-DA) was employed to distinguish the metabolic profile of rats in different groups and identify potential biomarkers.ResultsScore plots of PLS-DA exhibited that combined-therapy groups were significantly different from AMI group, whereas no differences were observed for mono-therapy groups. We found that AMI caused comprehensive metabolic changes involving stimulation of glycolysis, suppression of fatty acid oxidation, together with disturbed metabolism of arachidonic acid, linoleate, leukotriene, glycerophospholipid, phosphatidylinositol phosphate, and some amino acids. ?-hydroxybutyrate, cholines and glucose were regulated by mono-therapy of schizandrin and ginsenosides respectively. Besides these metabolites, combined-therapy ameliorated more of the AMI-induced metabolic changes including glycerol, and O-acetyl glycoprotein. A remarkable reduction of lactate suggested the therapeutic effect of combined-therapy through improving myocardial energy metabolism.ConclusionsThis study provided novel metabonomic insights on the mechanism of synergistic cardioprotection of combined-therapy with ginsenosides, schizandrin, and ophiopogonin D, and demonstrated the potential of discovering new drugs by combining bioactive components from traditional Chinese formula.

Dataset Information

Doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection by Mito-Q.

Publications

Doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection by Mito-Q.

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