Carvedilol Phenocopies PGC-1α Overexpression to Alleviate Oxidative Stress, Mitochondrial Dysfunction and Prevent Doxorubicin-Induced Toxicity in Human iPSC-Derived Cardiomyocytes
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals and Reagents
2.2. Cell Culture
2.3. Human iPSCs
2.3.1. Reprogramming Human Fibroblasts to iPSCs
2.3.2. iPSC Culture
2.3.3. iPSC-CM Differentiation
2.4. Determination of Cell Viability
2.5. Caspase 3/7 Assay
2.6. Detection of Mitochondrial Oxidants
2.7. Immunocytochemistry
2.8. Western Blot Analysis
2.9. Quantitative Polymerase Chain Reaction (qPCR)
2.10. Measurement of Mitochondrial Oxygen Consumption Rate
2.11. Measurement of Intracellular Reduced Thiols
2.12. Statistical Analysis
3. Results
3.1. Carvedilol Exerts Cardioprotective Effects from CTRTOX in Rat Cardiomyoblasts and Human iPSC-CMs
3.1.1. Cell Viability Assay
3.1.2. Apoptosis Assay
3.2. Carvedilol Pretreatment Decreases Levels of Mitochondrial Oxidants following DOX Exposure in H9c2 and Human iPSC-CMs
3.3. Carvedilol Pretreatment Sustains Levels of Cytosolic Keap1 and Decreased Nuclear Translocation of Nrf2 in DOX-Treated Rat Cardiomyoblasts and Human iPSC-CMs
3.4. DOX Treatment Induces Expression of Nrf2-Regulated Genes in Human iPSC-CMs
3.5. Carvedilol Pretreatment Prevents DOX-Induced Decreased Levels of Total Reduced Thiols in H9c2 Cells
3.6. Carvedilol Prevents DOX-Induced Suppression of Mitochondrial Respiratory Function in Human iPSC-CMs
3.7. PGC-1α Overexpression Recapitulates the Pharmacological Prevention by Carvedilol of DOX-Induced Mitochondrial Dysfunction in Human iPSC-CMs
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene | Forward (5′–3′) | Reverse (5′–3′) |
---|---|---|
Human Nqo1 | CCTGCCATTCTGAAAGGCTGGT | GTGGTGATGGAAAGCACTGCCT |
Human HMOX1 | CCAGGCAGAGAATGCTGAGTTC | AAGACTGGGCTCTCCTTGTTGC |
Human Catalase | GTGCGGAGATTCAACACTGCCA | CGGCAATGTTCTCACACAGACG |
Human SOD2 | CTGGACAAACCTCAGCCCTAAC | AACCTGAGCCTTGGACACCAAC |
Human SOD1 | CTCACTCTCAGGAGACCATTGC | CCACAAGCCAAACGACTTCCAG |
Human Keap1 | CAACTTCGCTGAGCAGATTGGC | TGATGAGGGTCACCAGTTGGCA |
Human GAPDH | TCCAAAATCAAGTGGGGCGA | TGATGACCCTTTTGGCTCCC |
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Uche, N.; Dai, Q.; Lai, S.; Kolander, K.; Thao, M.; Schibly, E.; Sendaydiego, X.; Zielonka, J.; Benjamin, I.J. Carvedilol Phenocopies PGC-1α Overexpression to Alleviate Oxidative Stress, Mitochondrial Dysfunction and Prevent Doxorubicin-Induced Toxicity in Human iPSC-Derived Cardiomyocytes. Antioxidants 2023, 12, 1585. https://doi.org/10.3390/antiox12081585
Uche N, Dai Q, Lai S, Kolander K, Thao M, Schibly E, Sendaydiego X, Zielonka J, Benjamin IJ. Carvedilol Phenocopies PGC-1α Overexpression to Alleviate Oxidative Stress, Mitochondrial Dysfunction and Prevent Doxorubicin-Induced Toxicity in Human iPSC-Derived Cardiomyocytes. Antioxidants. 2023; 12(8):1585. https://doi.org/10.3390/antiox12081585
Chicago/Turabian StyleUche, Nnamdi, Qiang Dai, Shuping Lai, Kurt Kolander, Mai Thao, Elizabeth Schibly, Xavier Sendaydiego, Jacek Zielonka, and Ivor J. Benjamin. 2023. "Carvedilol Phenocopies PGC-1α Overexpression to Alleviate Oxidative Stress, Mitochondrial Dysfunction and Prevent Doxorubicin-Induced Toxicity in Human iPSC-Derived Cardiomyocytes" Antioxidants 12, no. 8: 1585. https://doi.org/10.3390/antiox12081585