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Sex-related differences in delayed doxorubicin-induced cardiac dysfunction in C57BL/6 mice

  • Organ Toxicity and Mechanisms
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Abstract

Cancer survivors may experience long-term cardiovascular complications due to chemotherapeutic drugs such as doxorubicin (DOX). The exact mechanism of delayed DOX-induced cardiotoxicity has not been fully elucidated. Sex is an important risk factor for DOX-induced cardiotoxicity. In the current study, we identified sex differences in delayed DOX-induced cardiotoxicity and determined the underlying molecular determinants of the observed sexual dimorphism. Five-week-old male and female mice were administered intraperitoneal injections of DOX (4 mg/kg/week) or saline for 6 weeks. Echocardiography was performed 5 weeks after the last dose of DOX to evaluate cardiac function. Thereafter, mice were sacrificed and gene expression of markers of apoptosis, senescence, and inflammation was measured by PCR in hearts and livers. Proteomic profiling of the heart from both sexes was conducted to determine differentially expressed proteins (DEPs). Only DOX-treated male, but not female, mice demonstrated cardiac dysfunction, cardiac atrophy, and upregulated cardiac expression of Nppb and Myh7. No sex-related differences were observed in DOX-induced expression of most apoptotic, senescence, and pro-inflammatory markers. However, the gene expression of Trp53 was significantly reduced in hearts of DOX-treated female mice only. The anti-inflammatory marker Il-10 was significantly reduced in hearts of DOX-treated male mice only, while the pro-inflammatory marker Il-1α was significantly reduced in livers of DOX-treated female mice only. Gene expression of Tnf-α was reduced in hearts of both DOX-treated male and female mice. Proteomic analysis identified several DEPs after DOX treatment in a sex-specific manner, including anti-inflammatory acute phase proteins. This is the first study to assess sex-specific proteomic changes in a mouse model of delayed DOX-induced cardiotoxicity. Our proteomic analysis identified several sexually dimorphic DEPs, many of which are associated with the anti-inflammatory marker Il-10.

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The raw data supporting the conclusion of this article will be made available by the authors, without undue reservation.

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Acknowledgements

We thank LeeAnn Higgins, Todd Markowski, and Cesar Anguaya Velasquez in the Center for Metabolomics and Proteomics at the University of Minnesota for providing services related to the generation of quantitative proteomics data. The Orbitrap Eclipse instrumentation platform used in this work was purchased through High-end Instrumentation Grant S10OD028717 from the NIH. Experiments using the NanoDrop 8000 and QuantStudio 5 were performed with staff support at the University of Minnesota Genomics Center. Experiments using the Vevo2100 and Amersham Imager were supported by the resources and staff at the University of Minnesota University Imaging Centers (UIC). SCR_020997. We thank Ms. Engie S. El-Sawaf for her help with western blotting experiments.

Funding

This research is supported by the National Heart, Lung, and Blood Institute, Grant R01HL151740 (B.N.Z) and National Cancer Institute, Grant R01CA229618 (R. S. H). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. R.S. H. also receives support from NIH/NCI Grant R01CA204856, the University of Minnesota (UMN) Office of Academic Clinical Affairs (OACA) Faculty Research Development Grant, UMN College of Pharmacy SURRGE award and the UMN OACA Grant-in-Aid Program (GIA) award. I.Y.A. is supported by the Doctoral Dissertation Fellowship (DDF) offered by the University of Minnesota and the Bighley Graduate Fellowship from the College of Pharmacy.

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  1. Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, MN, 55455, USA

    Ibrahim Y. Abdelgawad, Benu George, Marianne K. O. Grant, Yingbo Huang, Yuting Shan, R. Stephanie Huang & Beshay N. Zordoky

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Conceptualization, BNZ and IYA; methodology, IYA and MKOG; formal analysis, IYA, BG, YS, and YH; data curation, IYA, MKOG, BG, YS, and YH; writing-original draft preparation, IYA, BG; writing-review and editing, IYA, BG, YH, YS, MKOG, RSH, and BNZ; supervision, BNZ; project administration, MKOG and BNZ; funding acquisition, BNZ. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Beshay N. Zordoky.

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Experimental procedures were conducted according to the ethical guidelines for the care and use of laboratory animals. All animal procedures in this study were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Minnesota (Protocol ID: 1807-36187A).

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Supplementary file 1. Fig. S1

: Hearts were harvested from male and female mice 6 weeks following the administration of 4 mg/kg/week DOX or an equivalent volume of sterile saline for 6 weeks (n = 5–8 per group). Following the extraction of total RNA, the mRNA expression of inflammatory markers, including a Pai-1, b Mcp-1, and c Mmp-13. (DOCX 144 kb)

Supplementary file 2. Online Resource 1

: Proteomics results spreadsheets. (XLSM 769 kb)

Supplementary file 3. Online Resource 2

: Uncropped western blot images for Fig. 8. (PPTX 12715 kb)

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Abdelgawad, I.Y., George, B., Grant, M.K.O. et al. Sex-related differences in delayed doxorubicin-induced cardiac dysfunction in C57BL/6 mice. Arch Toxicol 98, 1191–1208 (2024). https://doi.org/10.1007/s00204-023-03678-y

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