Abstract
Although anthracyclines improve the long-term survival rate of patients with cancer, severe and irreversible myocardial damage limits their clinical application. Amino acid (AA) metabolism in cardiomyocytes can be altered under pathological conditions. Therefore, exploring the AA metabolic signature in anthracycline-induced cardiotoxicity (AIC) is important for identifying novel mechanisms. We established mouse and cellular models of Adriamycin (ADR)-induced cardiac injury. We observed a decreased expression of troponins I (cTnI) after ADR treatment and ADR accelerated the degradation of cTnI, implying that AA metabolism could be altered in AIC. Using a targeted AA metabolomics approach based on ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS), the AA metabolic signatures in the sera of AIC mice and supernatant samples of ADR-treated H9c2 cardiomyocytes were analyzed. The levels of 14 AA metabolites were altered in ADR-treated mice (p < 0.05). Via bioinformatics analysis, we identified nine differential AA metabolites in mice and five differential AA metabolites in ADR-treated H9c2 cardiomyocytes. Three AAs with increased levels (l-glutamate, l-serine, and l-tyrosine) overlapped in the two models, suggesting a possible mechanism of AA metabolic impairment during AIC. The metabolic pathways perturbed by AIC involved aminoacyl-tRNA biosynthesis and alanine, aspartate, and glutamate metabolism. Our data suggests that ADR perturbed AA metabolism in AIC models. Moreover, the targeted AA metabolomics approach based on UPLC-MS/MS can be a unique platform to provide new clues for the prevention and treatment of AIC.
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All data generated or analysed during this study are included in this published article and its supplementary information files.
Abbreviations
- ADR:
-
Adriamycin
- AIC:
-
Anthracycline-induced cardiotoxicity
- AA:
-
Amino acid
- cTnI:
-
Cardiac troponin I
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We thank Joe Barber Jr., PhD, for basic language editing of a draft of this manuscript.
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This study was supported by the National Natural Science Foundation of China (No. 81870196).
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M. J., W. Q., and M. S. conceived and designed the study. W. Q. and M. S. provided financial supports. W. L. and S. L. performed most of the experiments, analyzed the data, and wrote the manuscript. Z. C. performed the cell experiments. Y. S. assisted with performing the animal experiments. All authors have read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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Li, W., Li, S., Cao, Z. et al. Exploration of the amino acid metabolic signature in anthracycline-induced cardiotoxicity using an optimized targeted metabolomics approach based on UPLC-MS/MS. Naunyn-Schmiedeberg's Arch Pharmacol 395, 1209–1224 (2022). https://doi.org/10.1007/s00210-022-02271-x
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DOI: https://doi.org/10.1007/s00210-022-02271-x