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A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
Microarray and Co-expression Network Analysis of Genes Associated with Acute Doxorubicin Cardiomyopathy in Mice
Sheng-Nan Wei1,2,3, Wen-Jie Zhao1,2,3, Xiang-Jun Zeng1,2,3
1Department 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.
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.
Insights
Doxorubicin (DOX) causes heart damage by disrupting glucose metabolism. The gene 2,3-bisphosphoglycerate mutase (Bpgm) appears central to this DOX-induced cardiotoxicity, offering potential therapeutic targets.
Area of Science:
- Cardiology
- Molecular Biology
- Genomics
Background:
- Doxorubicin (DOX) is a vital chemotherapy agent, but its clinical use is restricted by dose-dependent cardiotoxicity.
- The precise molecular mechanisms driving DOX-induced cardiotoxicity remain incompletely understood.
Purpose of the Study:
- To investigate the impact of DOX on global cardiac gene expression.
- To identify key molecular pathways and genes involved in DOX cardiotoxicity.
Main Methods:
- Mice received a single intraperitoneal injection of DOX (15 mg/kg) to induce acute cardiotoxicity.
- Cardiac function, apoptosis, and myocardial glucose/ATP levels were assessed.
- Microarray analysis identified differential gene expression, with key findings validated by qPCR.
- Experiments were replicated in cultured cardiomyocytes.
Main Results:
- DOX administration led to impaired cardiac function, increased cardiomyocyte apoptosis, and reduced myocardial glucose and ATP levels.
- Microarray analysis revealed significant alterations in gene expression, with 747 genes upregulated and 438 downregulated.
- Genes involved in metabolic pathways, particularly glucose metabolism (e.g., 2,3-bisphosphoglycerate mutase [Bpgm], hexokinase 2), were prominently affected.
- Gene co-expression network analysis highlighted Bpgm as a potential core factor in DOX cardiomyopathy.
Conclusions:
- DOX-induced cardiotoxicity is associated with significant disruptions in cardiac glucose metabolism.
- The gene 2,3-bisphosphoglycerate mutase (Bpgm) plays a critical role in the pathogenesis of DOX-induced cardiotoxicity.
- Targeting glucose metabolism pathways, especially Bpgm, may offer novel therapeutic strategies for mitigating DOX cardiotoxicity.
