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Microarray and Co-expression Network Analysis of Genes Associated with Acute Doxorubicin Cardiomyopathy in Mice

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Abstract

Clinical use of doxorubicin (DOX) in cancer therapy is limited by its dose-dependent cardiotoxicity. But molecular mechanisms underlying this phenomenon have not been well defined. This study was to investigate the effect of DOX on the changes of global genomics in hearts. Acute cardiotoxicity was induced by giving C57BL/6J mice a single intraperitoneal injection of DOX (15 mg/kg). Cardiac function and apoptosis were monitored using echocardiography and TUNEL assay at days 1, 3 and 5. Myocardial glucose and ATP levels were measured. Microarray assays were used to screen gene expression profiles in the hearts at day 5, and the results were confirmed with qPCR analysis. DOX administration caused decreased cardiac function, increased cardiomyocyte apoptosis and decreased glucose and ATP levels. Microarrays showed 747 up-regulated genes and 438 down-regulated genes involved in seven main functional categories. Among them, metabolic pathway was the most affected by DOX. Several key genes, including 2,3-bisphosphoglycerate mutase (Bpgm), hexokinase 2, pyruvate dehydrogenase kinase, isoenzyme 4 and fructose-2,6-bisphosphate 2-phosphatase, are closely related to glucose metabolism. Gene co-expression networks suggested the core role of Bpgm in DOX cardiomyopathy. These results obtained in mice were further confirmed in cultured cardiomyocytes. In conclusion, genes involved in glucose metabolism, especially Bpgm, may play a central role in the pathogenesis of DOX-induced cardiotoxicity.

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Acknowledgments

This study was supported by Grants from National Natural Science Foundation of China (81330003, 81025001) and Chang Jiang Scholar Program.

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Authors and Affiliations

  1. Department of Physiology and Pathophysiology, Beijing Anzhen Hospital the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing, 100069, China

    Sheng-Nan Wei, Wen-Jie Zhao, Xiang-Jun Zeng, Jie Du & Hui-Hua Li

  2. Department of Cardiology, Chaoyang Hospital, Capital Medical University, Beijing, 100069, China

    Sheng-Nan Wei, Wen-Jie Zhao, Xiang-Jun Zeng, Jie Du & Hui-Hua Li

  3. Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, China

    Sheng-Nan Wei, Wen-Jie Zhao, Xiang-Jun Zeng, Jie Du & Hui-Hua Li

  4. Department of Physiology and Pathophysiology, Xi’an Jiaotong University Cardiovascular Research Center, Xi’an Jiaotong University School of Medicine, Xi’an, 710061, China

    Yu-Ming Kang

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  1. Sheng-Nan Wei
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Correspondence to Hui-Hua Li.

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12012_2014_9306_MOESM1_ESM.tif

Supplement Fig. 1. Growth parameters, histochemical analysis and some blood parameters of saline and DOX-treated WT mice. a. Growth parameters such as BW, HW and HW/TL were detected. Data are the mean ± SEM (n = 4–7). *P<0.05, #P<0.01 vs. control. b. Histology of heart tissue after DOX injection (15 mg/kg) using hematoxylin and eosin (H&E) staining. Vacuole formation was pointed out with red arrows. Bar: 20 µm, magnification: ×400. c and d. Blood parameters including total hemoglobin and blood glucose were measured. Data are the mean ± SEM (n = 3–7). *P<0.05, #P<0.01 vs. control. BW indicates body weight; HW, heart weight; HW/TL, heart weight/tibia length. (TIFF 17264 kb)

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Wei, SN., Zhao, WJ., Zeng, XJ. et al. Microarray and Co-expression Network Analysis of Genes Associated with Acute Doxorubicin Cardiomyopathy in Mice. Cardiovasc Toxicol 15, 377–393 (2015). https://doi.org/10.1007/s12012-014-9306-7

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