Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition
Abstract
:1. Introduction
2. Results
2.1. Biological Response to dnATG5 and Doxorubicin Exposure
2.2. Validation of the Experimental Treatment
2.3. Inhibition of Autophagosome Formation Protects against Acute DOX-Induced Cardiomyopathy
2.4. Inhibition of Autophagosome Formation Protects against Acute DOX-Induced Mitochondrial Dysfunction and ROS Production
3. Discussion
3.1. DOX-Induced Autophagy Signaling
3.2. Cardiac Function and DOX-Induced Autophagy
3.3. Relationship between Autophagy and Oxidative Stress
4. Methods
4.1. Experimental Animals
4.2. Echocardiography
4.3. Cardiac Muscle Permeabilization
4.4. Mitochondrial Respiration
4.5. Mitochondrial ROS Emission
4.6. Western Blot Analysis
4.7. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Saline-Saline | Saline-DOX | dnATG5-DOX | |
---|---|---|---|
2-Day | |||
Initial weight (g) | 278.6 ± 3.3 | 283.1 ± 5.5 | 280.1 ± 3.4 |
Treatment weight (g) | 296.5 ± 4.4 | 302.8 ± 5.1 | 299.9 ± 4.5 |
Final weight (g) | 295.9 ± 4.5 | 287.1 ± 6.6 | 290.5 ± 6.3 |
Heart weight (mg) | 870.5 ± 18.8 | 792.4 ± 27.3 | 822.0 ± 28.1 |
9-Day | |||
Initial weight (g) | 268.8 ± 3.6 | 273.0 ± 5.8 | 278.3 ± 3.3 |
Treatment weight (g) | 286.5 ± 6.8 | 287.4 ± 6.0 | 293.3 ± 4.8 |
Final weight (g) | 282.6 ± 5.6 | 229.4 ± 13.8 # | 229.0 ± 5.9 # |
Heart weight (mg) | 796.0 ± 30.6 | 597.5 ± 43.1 # | 581.1 ± 13.5 # |
Saline-Saline | Saline-DOX | dnATG5-DOX | |
---|---|---|---|
2-Day | |||
SWTd (mm) | 1.41 ± 0.03 | 1.24 ± 0.05 # | 1.24 ± 0.04 # |
SWTs (mm) | 2.54 ± 0.07 | 2.13 ± 0.08 # | 2.25 ± 0.09 # |
PWTd (mm) | 1.43 ± 0.04 | 1.36 ± 0.09 | 1.36 ± 0.05 |
PWTs (mm) | 2.54 ± 0.06 | 1.90 ± 0.11 # | 2.16 ± 0.09 # |
9-Day | |||
SWTd (mm) | 1.74 ± 0.07 | 2.08 ± 0.23 | 1.95 ± 0.17 |
SWTs (mm) | 2.80 ± 0.10 | 2.85 ± 0.20 | 2.63 ± 0.18 |
PWTd (mm) | 1.81 ± 0.07 | 2.04 ± 0.15 | 2.30 ± 0.27 |
PWTs (mm) | 2.86 ± 0.12 | 2.91 ± 0.20 | 3.21 ± 0.36 |
Saline-Saline | Saline-DOX | dnATG5-DOX | |
---|---|---|---|
2-Day | |||
State 3 (nmoles O2/mg/min) | 9.81 ± 0.83 | 9.75 ± 0.67 | 10.60 ± 0.66 |
State 4 (nmoles O2/mg/min) | 2.13 ± 0.23 | 3.79 ± 0.24 * | 2.67 ± 0.13 |
RCR (State 3/State 4) | 4.93 ± 0.37 | 2.67 ± 0.26 * | 4.06 ± 0.23 |
9-Day | |||
State 3 (nmoles O2/mg/min) | 9.50 ± 1.57 | 8.40 ± 1.12 | 11.29 ± 1.14 |
State 4 (nmoles O2/mg/min) | 2.16 ± 0.41 | 2.37 ± 0.20 | 3.21 ± 0.30 |
RCR (State 3/State 4) | 4.53 ± 0.18 | 3.52 ± 0.27 # | 3.54 ± 0.20 # |
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Montalvo, R.N.; Doerr, V.; Kwon, O.S.; Talbert, E.E.; Yoo, J.-K.; Hwang, M.-H.; Nguyen, B.L.; Christou, D.D.; Kavazis, A.N.; Smuder, A.J. Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition. Int. J. Mol. Sci. 2020, 21, 8105. https://doi.org/10.3390/ijms21218105
Montalvo RN, Doerr V, Kwon OS, Talbert EE, Yoo J-K, Hwang M-H, Nguyen BL, Christou DD, Kavazis AN, Smuder AJ. Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition. International Journal of Molecular Sciences. 2020; 21(21):8105. https://doi.org/10.3390/ijms21218105
Chicago/Turabian StyleMontalvo, Ryan N., Vivian Doerr, Oh Sung Kwon, Erin E. Talbert, Jeung-Ki Yoo, Moon-Hyon Hwang, Branden L. Nguyen, Demetra D. Christou, Andreas N. Kavazis, and Ashley J. Smuder. 2020. "Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition" International Journal of Molecular Sciences 21, no. 21: 8105. https://doi.org/10.3390/ijms21218105