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2000
Volume 20, Issue 9
  • ISSN: 1573-4129
  • E-ISSN: 1875-676X

Abstract

Background

Doxorubicin (DOX) causes lethal cardiotoxicity, which limits its clinical utility. The molecular mechanisms and effective strategies to combat its cardiotoxicity need further exploration. DT-010, a novel conjugate of danshensu (DSS) and tetramethylpyrazine (TMP), is considered a promising candidate for treating DOX-induced cardiotoxicity. In this study, we aimed to investigate the underlying molecular mechanisms of DOX-induced cardiotoxicity and the cardioprotective effects of DT-010.

Methods

Isobaric tags for relative and absolute quantitation (iTRAQ) in proteomics analysis was employed to analyze the differentially expressed proteins in DOX-injuried hearts. Gene ontology (GO) enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were carried out to evaluated the potential mechanisms of DOX-induced cardiotoxicity. The effects of NCAM1 on DOX-induced cardiotoxicity in H9c2 cells, as well as the cardioprotection of DT-010 were assessed through NACM1siRNA transfection, cell viability assay, cell apoptosis staining, reactive oxygen species measurement, and western blotting.

Results

Proteomics analysis revealed that several signaling pathways, including the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, were involved in DOX-induced cardiotoxicity. NCAM1 is one of the significantly changed proteins. DT-010 treatment regulated NCAM1 protein expression. Silencing NCAM1 in DOX-treated H9c2 cells decreased cell viability, increased cell apoptosis and reactive oxygen species (ROS) generation, and attenuated the cardioprotective effects of DT-010. Furthermore, NCAM1 knockdown promoted p38 activation and inhibited the expressions of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and heme oxygenase-1 (HO-1) in DOX-treated cells.

Conclusion

These findings indicate a definite role of NCAM1 in DOX-induced cardiotoxicity and DT-010-exerted cardioprotection, which is mediated through the p38 and Sirt1/PGC-1α/HO-1 pathway.

© 2024 Bentham Science Publishers
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2025-09-08

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iTRAQ-based Proteomic Analysis Unveils NCAM1 as a Novel Regulator in Doxorubicin-induced Cardiotoxicity and DT-010-exerted Cardioprotection
Current Pharmaceutical Analysis 20, 966 (2024); https://doi.org/10.2174/0115734129331758241022113026
/content/journals/cpa/10.2174/0115734129331758241022113026
/content/journals/cpa/10.2174/0115734129331758241022113026
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  • Article Type:     Research Article
Keyword(s): cardiotoxicity; doxorubicin; DT-010; iTRAQ-based proteomics analysis; neural cell adhesion molecule 1; Sirt1/PGC-1α/HO-1

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