Anthocyanin Attenuates Doxorubicin-Induced Cardiomyotoxicity via Estrogen Receptor-α/β and Stabilizes HSF1 to Inhibit the IGF-IIR Apoptotic Pathway
"> Figure 1
<p>Dox stimulated the insulin-like growth factor II receptor (IGF-IIR) apoptotic pathway and repressed the expression of the estrogen receptors (ERs). (<b>A</b>) H9c2 cells are treated with different concentrations of doxorubicin for 24 h; the protein level of CHIP, HSF1, IGF-IIR, active caspase 3, and p-Akt is measured by immunoblotting. Quantification of these results is shown right (<span class="html-italic">n</span> = 3). * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01 and *** <span class="html-italic">p</span> < 0.001; (<b>B</b>) H9c2 cells are treated with different concentrations of doxorubicin for 24 h. The cell viability was measured by MTT assay. Quantification of these results is shown (<span class="html-italic">n</span> = 3). * <span class="html-italic">p</span> < 0.05 and ** <span class="html-italic">p</span> < 0.01; (<b>C</b>) H9c2 cells are treated with different concentrations of doxorubicin for 24 h. The caspase-3 activities were measured by PhiPhiLux<sup>®</sup>-G1D2 assay. Quantification of these results is shown (<span class="html-italic">n</span> = 3). * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01 and *** <span class="html-italic">p</span> < 0.001; (<b>D</b>) H9c2 cells are treated with different concentrations of doxorubicin for 24 h. The apoptotic cells were measured by TUNEL assay. Quantification of these results is shown (<span class="html-italic">n</span> = 3). * <span class="html-italic">p</span> < 0.05 and *** <span class="html-italic">p</span> < 0.001; (<b>E</b>) H9c2 cells are treated with siRNA against CHIP for 24 h, and treated with 1 µM doxorubicin for further 24 hrs. The protein level of CHIP, HSF1, IGF-IIR and p-NFκB is measured by immunoblotting; and (<b>F</b>) H9c2 cells are treated with different concentrations of doxorubicin for 24 h, the protein level of the ERs is measured by immunoblotting. Quantification of these results is shown (<span class="html-italic">n</span> = 3). * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01 and *** <span class="html-italic">p</span> < 0.001. These data were obtained from at least three independent experiments and values represent the means ± S.D.</p> "> Figure 2
<p>Anthocyanin enhanced ER expression and attenuated the IGF-IIR apoptotic pathway. (<b>A</b>) After H9c2 cells are treated with 1 µM doxorubicin for 6 and 12 h, they are washed with PBS, and then, fresh medium is added, followed by post-treatment with anthocyanin 20 and 40 µg/mL and incubation of cells for 24 h after doxorubicin treatment. The ERα and ERβ protein levels were measured. Quantification of these results is shown right (<span class="html-italic">n</span> = 3). * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01 and *** <span class="html-italic">p</span> < 0.001; (<b>B</b>) after H9c2 cells are treated with 1 µM doxorubicin for 6 and 12 h, they are washed with PBS, and then, fresh medium is added, followed by post-treatment with anthocyanin 20 and 40 µg/mL and incubation of cells for 24 h after doxorubicin treatment. Proteins involved in IGF-IIR apoptotic pathway were measured by immunoblotting. Quantification of these results is shown right (<span class="html-italic">n</span> = 3). * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01 and *** <span class="html-italic">p</span> < 0.001; and (<b>C</b>) after H9c2 cells are treated with 1 µM doxorubicin for 6 h, they are washed with PBS and fresh medium is added, followed by post-treatment with anthocyanin at 20 and 40 µg/mL, and incubation of cells for 18 h. The detection of apoptotic cells was determined by a TUNEL assay. Bars = 10 µm. Quantification of these results is shown right (<span class="html-italic">n</span> = 3). * <span class="html-italic">p</span> < 0.05 and *** <span class="html-italic">p</span> < 0.001. These data were obtained from at least three independent experiments and values represent the means ± S.D.</p> "> Figure 3
<p>The effects of anthocyanin treatment were attenuated by the estrogen receptor antagonist ICI 182,780. (<b>A</b>) H9c2 cells were pre-treated with 1 µM ICI 182,780 for 1 h, followed by treatment with doxorubicin at 1 µM and incubation for 6 h. Then, the medium was changed to fresh medium, anthocyanin at 40 µg/mL was added, and the cells were incubated for 18 h before measurement by immunoblotting. Quantification of these results is shown right (<span class="html-italic">n</span> = 3). * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01 and *** <span class="html-italic">p</span> < 0.001; (<b>B</b>) the level of SIRT1 protein expression after different concentrations of doxorubicin for 24 h was investigated by immunoblotting. Quantification of these results is shown (<span class="html-italic">n</span> = 3). * <span class="html-italic">p</span> < 0.05; (<b>C</b>) H9c2 cells were pre-treated with 1 µM ICI 182,780 for 1 h, followed by treatment with doxorubicin at 1 µM and incubation for 6 h. Then, the medium was changed to fresh medium, anthocyanin at 40 µg/mL was added, and the cells were incubated for 18 h before measurement by immunoblotting. Quantification of SIRT1 epxression is shown right (<span class="html-italic">n</span> = 3). * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01 and *** <span class="html-italic">p</span> < 0.001.</p> "> Figure 4
<p>Echocardiographic assessments and histopathological analysis of rat left ventricular cells after doxorubicin and anthocyanin treatment. (<b>A</b>) The schematic procedure of DOX and HSF1A administration; (<b>B</b>) histopathologic analysis of heart tissue sections stained with H and E. Magnification: 200×; bars = 50 µm. An enlarged interstitium was observed in the doxorubicin-treated rat hearts, and the arrows indicate the myocardial interstitium. The expression of TUNEL + cardiomyocytes and SIRT1 expression were evaluated by immunohistochemistry (IHC) and TUNEL assay. Quantification of TUNEL + cardiomyocytes from each group is shown right (<span class="html-italic">n</span> = 3 per group). These data were obtained from at least three independent experiments and values represent the means ± S.D. ** <span class="html-italic">p</span> < 0.01 and *** <span class="html-italic">p</span> < 0.001.</p> "> Figure 5
<p>Protein expression of the left ventricles of rat hearts after six weeks of doxorubicin and anthocyanin treatment. (<b>A</b>,<b>B</b>) The left ventricles of hearts were excised and homogenized. The cell lysates were quantified and analyzed via immunoblotting. The expression of the IGF-IIR signaling pathway protein and the expression of the apoptosis marker caspase-3 and ERs were estimated via immunoblotting. Quantification of the results is shown right (<span class="html-italic">n</span> = 3 per group). * <span class="html-italic">p</span> < 0.05 and ** <span class="html-italic">p</span> < 0.01; and (<b>C</b>) immunohistochemical detection of CHIP, active caspase-3 expression. Arrows indicated the expression of CHIP and active caspase-3, respectively. Magnification: 400×; bars = 10 µm.</p> "> Figure 6
<p>Schematic diagram of how ACN attenuates doxorubicin-induced cardiomyotoxicity through ERα/β to up-regulate CHIP-mediated HSF1 nuclear translocation and SIRT1-mediated HSF1 activation to inhibit the IGF-IIR apoptotic pathway.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Dox Stimulated IGF-IIR Apoptotic Pathway and Repressed ER Expression
2.2. ACN Rescued Dox-Induced up-Rregulation of the IGF-IIR-Mediated Apoptosis Pathway
2.3. Effects of ACN Were Attenuated by ER Antagonist ICI 182780
2.4. Function Recovering Effect of ACN in Dox-Treated Hearts in Vivo
2.5. Effects of Rat Left Ventricular Protein Expression as a Result of Dox and ACN Treatment in Vivo
3. Discussion
4. Materials and Methods
4.1. Chemicals and Antibodies
4.2. Cell Culture and Treatment
4.3. Western Blot Analysis
4.4. TdT-Mediated Digoxigenin-dUTP Nick-End Labeling (TUNEL) Assay
4.5. Cell Viability Assay
4.6. Flow Cytometric Analysis for Caspase-3 Activity
4.7. Animal Models
4.8. Tissue Extraction
4.9. Hematoxylin-Eosin Stain
4.10. Immunohistochemistry Staining
4.11. Statistical Analysis
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Cardiac Profiles | Control Group (n = 3) | Dox Group (n = 3) | Dox-CAN Group (n = 3) |
---|---|---|---|
LVIDd (mm) | 8.09 ± 0.08 | 7.15 ± 0.15 ** | 8.12 ± 0.22 ### |
LVIDs (mm) | 5.23 ± 0.57 | 4.11 ± 0.14 ** | 4.59 ± 0.35 |
LVPWd (mm) | 1.33 ± 0.07 | 0.96 ± 0.07 ** | 1.2 ± 0.07 # |
LVPWs (mm) | 2.18 ± 0.15 | 1.58 ± 0.15 * | 2.23 ± 0.23 # |
IVSd (mm) | 1.16 ± 0.01 | 0.97 ± 0.07 * | 1.21 ± 0.09 ## |
IVSs (mm) | 2.34 ± 0.08 | 1.69 ± 0.14 ** | 2.47 ± 0.26 ## |
EDV (Teich) | 1.28 ± 0.38 | 0.82 ± 0.05 | 1.19 ± 0.11 |
ESV (Teich) | 0.39 ± 0.11 | 1.23 ± 0.02 | 1.24 ± 0.06 |
EF (Teich) | 75.28 ± 2.29 | 62.32 ± 4.86 ** | 78.18 ± 1.72 ## |
%FS | 39 ± 2.57 | 31.38 ± 2.64 ** | 41.7 ± 1.47 ## |
LVd Mass (ASE) | 1.15 ± 0.06 | 0.96 ± 0.06 | 1.14 ± 0.1 |
LVs Mass (ASE) | 1.21 ± 0.09 | 1.02 ± 0.03 * | 1.2 ± 0.08 # |
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Huang, P.-C.; Kuo, W.-W.; Shen, C.-Y.; Chen, Y.-F.; Lin, Y.-M.; Ho, T.-J.; Padma, V.V.; Lo, J.-F.; Huang, C.-Y.; Huang, C.-Y. Anthocyanin Attenuates Doxorubicin-Induced Cardiomyotoxicity via Estrogen Receptor-α/β and Stabilizes HSF1 to Inhibit the IGF-IIR Apoptotic Pathway. Int. J. Mol. Sci. 2016, 17, 1588. https://doi.org/10.3390/ijms17091588
Huang P-C, Kuo W-W, Shen C-Y, Chen Y-F, Lin Y-M, Ho T-J, Padma VV, Lo J-F, Huang C-Y, Huang C-Y. Anthocyanin Attenuates Doxorubicin-Induced Cardiomyotoxicity via Estrogen Receptor-α/β and Stabilizes HSF1 to Inhibit the IGF-IIR Apoptotic Pathway. International Journal of Molecular Sciences. 2016; 17(9):1588. https://doi.org/10.3390/ijms17091588
Chicago/Turabian StyleHuang, Pei-Chen, Wei-Wen Kuo, Chia-Yao Shen, Yu-Feng Chen, Yueh-Min Lin, Tsung-Jung Ho, V. Vijaya Padma, Jeng-Fan Lo, Chih-Yang Huang, and Chih-Yang Huang. 2016. "Anthocyanin Attenuates Doxorubicin-Induced Cardiomyotoxicity via Estrogen Receptor-α/β and Stabilizes HSF1 to Inhibit the IGF-IIR Apoptotic Pathway" International Journal of Molecular Sciences 17, no. 9: 1588. https://doi.org/10.3390/ijms17091588