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Doxorubicin-induced cardiomyopathy associated with inhibition of autophagic degradation process and defects in mitochondrial respiration.

ABSTRACT: Doxorubicin (Dox) is a highly effective anticancer drug but cause acute ventricular dysfunction, and also induce late-onset cardiomyopathy and heart failure. Despite extensive studies, the pathogenic sequelae leading to the progression of Dox-associated cardiomyopathy remains unknown. We assessed temporal changes in autophagy, mitochondrial dynamics, and bioenergetics in mouse models of acute and chronic Dox-cardiomyopathy. Time course study of acute Dox-treatment showed accumulation of LC3B II in heart lysates. Autophagy flux assays confirmed that the Dox-induced accumulation of autophagosomes occurs due to blockage of the lysosomal degradation process. Dox-induced autophagosomes and autolysosome accumulation were confirmed in vivo by using GFP-LC3 and mRFP-GFP-LC3 transgenic (Tg) mice. Mitochondria isolated from acute Dox-treated hearts showed significant suppression of oxygen consumption rate (OCR). Chronic Dox-cardiotoxicity also exhibited time-dependent accumulation of LC3B II levels and increased accumulation of green puncta in GFP-LC3 Tg hearts. Mitochondria isolated from chronic Dox-treated hearts also showed significant suppression of mitochondrial OCR. The in vivo impairment of autophagic degradation process and mitochondrial dysfunction data were confirmed in vitro using cultured neonatal cardiomyocytes. Both acute and chronic Dox-associated cardiomyopathy involves a multifocal disease process resulting from autophagosomes and autolysosomes accumulation, altered expression of mitochondrial dynamics and oxidative phosphorylation regulatory proteins, and mitochondrial respiratory dysfunction.

SUBMITTER: Abdullah CS

PROVIDER: S-EPMC6376057 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Doxorubicin-induced cardiomyopathy associated with inhibition of autophagic degradation process and defects in mitochondrial respiration.

Abdullah Chowdhury S CS Alam Shafiul S Aishwarya Richa R Miriyala Sumitra S Bhuiyan Mohammad Alfrad Nobel MAN Panchatcharam Manikandan M Pattillo Christopher B CB Orr A Wayne AW Sadoshima Junichi J Hill Joseph A JA Bhuiyan Md Shenuarin MS

Scientific reports 20190214 1

Doxorubicin (Dox) is a highly effective anticancer drug but cause acute ventricular dysfunction, and also induce late-onset cardiomyopathy and heart failure. Despite extensive studies, the pathogenic sequelae leading to the progression of Dox-associated cardiomyopathy remains unknown. We assessed temporal changes in autophagy, mitochondrial dynamics, and bioenergetics in mouse models of acute and chronic Dox-cardiomyopathy. Time course study of acute Dox-treatment showed accumulation of LC3B II ...[more]

PMID: 30765730

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Project description:The aim of this study was to test the hypothesis that long-term dietary nitrate supplementation protects against doxorubicin-induced cardiomyopathy by improving ventricular function and reducing mitochondrial respiratory chain damage.Doxorubicin is a powerful anthracycline antibiotic used to treat divergent human neoplasms. Its clinical use is limited because of severe cardiotoxic side effects. Dietary nitrate and nitrite are essential nutrients for maintenance of steady-state tissue levels of nitric oxide and may play a therapeutic role in diseases associated with nitric oxide insufficiency or dysregulation. Dietary nitrate and nitrite supplementation alleviates myocardial injury caused by ischemia-reperfusion and cardiac arrest-resuscitation.Adult male CF-1 mice were given a single dose of doxorubicin (15 mg/kg intraperitoneally), and left ventricular contractile function was assessed 5 days later using both echocardiography and pressure-volume Millar catheterization. A nitrate supplementation regimen (1 g/l sodium nitrate in drinking water) was started 7 days before doxorubicin injection and continued thereafter. Cardiomyocyte necrosis and apoptosis, tissue lipid peroxidation, and plasma nitrate and nitrite levels were assessed. In addition, mitochondrial complex I activity, oxidative phosphorylation capacity, and hydrogen peroxide generation were determined in parallel experiments.Doxorubicin caused impairment of ventricular contractility and cell death, which were significantly reduced by nitrate supplementation (p < 0.05). These cardioprotective effects were associated with a significant decrease in tissue lipid peroxidation. Nitrate supplementation significantly preserved mitochondrial complex I activity and oxidative phosphorylation and attenuated hydrogen peroxide generation after doxorubicin treatment.Long-term oral intake of inorganic nitrate attenuates doxorubicin-induced ventricular dysfunction, cell death, oxidative stress, and mitochondrial respiratory chain damage. Nitrate could be a promising therapeutic agent against doxorubicin-induced cardiotoxicity.

Dataset Information

Doxorubicin-induced cardiomyopathy associated with inhibition of autophagic degradation process and defects in mitochondrial respiration.

Publications

Doxorubicin-induced cardiomyopathy associated with inhibition of autophagic degradation process and defects in mitochondrial respiration.

Similar Datasets

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