Sex Differences in Doxorubicin‐Induced Cardiotoxicity: Insights from Transcriptome Analysis

Author:

Su Qingqing1,Fu Min2,Xiao Wanli3,Zhao Huan4,Yu Yang1,Feng Jianguo3,Liu Yulin3,Wan Ying2,Yu Yajun1ORCID,Zhang Chunxiang12

Affiliation:

1. Key Laboratory of Medical Electrophysiology Ministry of Education Institute of Cardiovascular Research and Institute of Metabolic Diseases Southwest Medical University Luzhou Sichuan 646000 China

2. School of Basic Medical Science Southwest Medical University Luzhou Sichuan 646000 China

3. Department of Anesthesiology The Affiliated Hospital Southwest Medical University Luzhou 646000 China

4. Department of Oncology The First Affiliated Hospital of Zhengzhou University Zhengzhou Henan 450052 China

Abstract

AbstractMale patients have a higher risk of cardiotoxicity following doxorubicin (DOX) treatment than female patients. However, how this difference occurs at the transcriptome level remains unclear, and the mechanisms underlying these differences are understudied. This study aimed to describe the transcriptional patterns of males and females after DOX treatment and explore the possible mechanisms of sexual differences in DOX‐induced cardiotoxicity. Following DOX treatment, male mice exhibit more severe heart damage than female mice. Transcriptome analysis of mice with and without DOX treatment showed that differentially expressed genes (DEGs) are significantly different between males and females. The majority of DEGs are sex‐specific, and more DEGs are identified in males than females. A number of genes, including the oxidation‐related genes Gdf15 and Rbm3, exhibited altered expression either in males or females. Some other genes, including the ferroptosis‐related gene Cd74, changed their expression levels in both sexes, but at different scales. Biochemical experiments suggested that cardiomyocyte oxidation and ferroptosis may contribute to the sexual dimorphism of DOX‐induced cardiotoxicity. In summary, this study shows that, after exposure to DOX, males and females respond differently regarding the expression of hundreds of genes, including Gdf15, Rbm3, and Cd74, possibly explaining the sexual differences in DOX‐induced cardiotoxicity.

Publisher

Wiley

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