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Cyclovirobuxine D Attenuates Doxorubicin-Induced Cardiomyopathy by Suppression of Oxidative Damage and Mitochondrial Biogenesis Impairment.

Guo Q, Guo J, Yang R, Peng H, Zhao J, Li L, Peng S - Oxid Med Cell Longev (2015)

Bottom Line: Our results showed that CVB-D pretreatment markedly attenuated DOX-induced cardiac contractile dysfunction and histological alterations.CVB-D pretreatment ameliorated DOX-induced cardiac oxidative damage including lipid peroxidation and protein carbonylation and a decrease in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG).Moreover, CVB-D was found to prevent DOX-induced mitochondrial biogenesis impairment as evidenced by preservation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and nuclear respiratory factor 1 (NRF1), as well as mitochondrial DNA copy number.

View Article: PubMed Central - PubMed

Affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, 20 Dongdajie Street, Fengtai District, Beijing 100071, China ; Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China.

ABSTRACT
The clinical application of doxorubicin (DOX) is compromised by its cardiac toxic effect. Cyclovirobuxine D (CVB-D) is a steroid alkaloid extracted from a traditional Chinese medicine, Buxus microphylla. Our results showed that CVB-D pretreatment markedly attenuated DOX-induced cardiac contractile dysfunction and histological alterations. By using TUNEL assay and western blot analysis, we found that CVB-D pretreatment reduced DOX-induced apoptosis of myocardial cells and mitochondrial cytochrome c release to cytosol. CVB-D pretreatment ameliorated DOX-induced cardiac oxidative damage including lipid peroxidation and protein carbonylation and a decrease in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG). Moreover, CVB-D was found to prevent DOX-induced mitochondrial biogenesis impairment as evidenced by preservation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and nuclear respiratory factor 1 (NRF1), as well as mitochondrial DNA copy number. These findings demonstrate that CVB-D protects against DOX-induced cardiomyopathy, at least in part, by suppression of oxidative damage and mitochondrial biogenesis impairment.

No MeSH data available.


Related in: MedlinePlus

CVB-D inhibits cytochrome c release from mitochondria into cytosol in the heart. (a) Representative blots of cytochrome c in cardiac mitochondrial and cytosolic fractions. (b) Quantitative analysis of cytochrome c protein expression. ∗P < 0.05 versus the control group; #P < 0.05 versus the DOX group.
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fig4: CVB-D inhibits cytochrome c release from mitochondria into cytosol in the heart. (a) Representative blots of cytochrome c in cardiac mitochondrial and cytosolic fractions. (b) Quantitative analysis of cytochrome c protein expression. ∗P < 0.05 versus the control group; #P < 0.05 versus the DOX group.

Mentions: Mitochondrial cytochrome c release into cytosol plays a pivotal role in DOX-induced apoptosis. As shown in Figure 4, western blot analysis revealed that DOX treatment significantly increased cytosolic concentrations of cytochrome c with a decrease in mitochondria. Pretreatment with CVB-D preserved cytochrome c in mitochondria against DOX, as evidenced by significantly improved cytochrome c release into cytosol in CVB-D + DOX group. CVB-D alone had no effect on the distribution of cardiac cytochrome c in mitochondria and cytosol. These findings are consistent with the results from TUNEL assay and correlate with cardiac function alterations.


Cyclovirobuxine D Attenuates Doxorubicin-Induced Cardiomyopathy by Suppression of Oxidative Damage and Mitochondrial Biogenesis Impairment.

Guo Q, Guo J, Yang R, Peng H, Zhao J, Li L, Peng S - Oxid Med Cell Longev (2015)

CVB-D inhibits cytochrome c release from mitochondria into cytosol in the heart. (a) Representative blots of cytochrome c in cardiac mitochondrial and cytosolic fractions. (b) Quantitative analysis of cytochrome c protein expression. ∗P < 0.05 versus the control group; #P < 0.05 versus the DOX group.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4446494&req=5

fig4: CVB-D inhibits cytochrome c release from mitochondria into cytosol in the heart. (a) Representative blots of cytochrome c in cardiac mitochondrial and cytosolic fractions. (b) Quantitative analysis of cytochrome c protein expression. ∗P < 0.05 versus the control group; #P < 0.05 versus the DOX group.
Mentions: Mitochondrial cytochrome c release into cytosol plays a pivotal role in DOX-induced apoptosis. As shown in Figure 4, western blot analysis revealed that DOX treatment significantly increased cytosolic concentrations of cytochrome c with a decrease in mitochondria. Pretreatment with CVB-D preserved cytochrome c in mitochondria against DOX, as evidenced by significantly improved cytochrome c release into cytosol in CVB-D + DOX group. CVB-D alone had no effect on the distribution of cardiac cytochrome c in mitochondria and cytosol. These findings are consistent with the results from TUNEL assay and correlate with cardiac function alterations.

Bottom Line: Our results showed that CVB-D pretreatment markedly attenuated DOX-induced cardiac contractile dysfunction and histological alterations.CVB-D pretreatment ameliorated DOX-induced cardiac oxidative damage including lipid peroxidation and protein carbonylation and a decrease in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG).Moreover, CVB-D was found to prevent DOX-induced mitochondrial biogenesis impairment as evidenced by preservation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and nuclear respiratory factor 1 (NRF1), as well as mitochondrial DNA copy number.

View Article: PubMed Central - PubMed

Affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, 20 Dongdajie Street, Fengtai District, Beijing 100071, China ; Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China.

ABSTRACT
The clinical application of doxorubicin (DOX) is compromised by its cardiac toxic effect. Cyclovirobuxine D (CVB-D) is a steroid alkaloid extracted from a traditional Chinese medicine, Buxus microphylla. Our results showed that CVB-D pretreatment markedly attenuated DOX-induced cardiac contractile dysfunction and histological alterations. By using TUNEL assay and western blot analysis, we found that CVB-D pretreatment reduced DOX-induced apoptosis of myocardial cells and mitochondrial cytochrome c release to cytosol. CVB-D pretreatment ameliorated DOX-induced cardiac oxidative damage including lipid peroxidation and protein carbonylation and a decrease in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG). Moreover, CVB-D was found to prevent DOX-induced mitochondrial biogenesis impairment as evidenced by preservation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and nuclear respiratory factor 1 (NRF1), as well as mitochondrial DNA copy number. These findings demonstrate that CVB-D protects against DOX-induced cardiomyopathy, at least in part, by suppression of oxidative damage and mitochondrial biogenesis impairment.

No MeSH data available.


Related in: MedlinePlus