title: Microarray and Co-expression Network Analysis of Genes Associated with Acute Doxorubicin Cardiomyopathy in Mice.
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.
authors.affiliation: 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.|Department of Cardiology, Chaoyang Hospital, Capital Medical University, Beijing, 100069, China.|Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, China.
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Wei
authors.affiliation: 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.|Department of Cardiology, Chaoyang Hospital, Capital Medical University, Beijing, 100069, China.|Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, China.
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Zhao
authors.affiliation: 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.|Department of Cardiology, Chaoyang Hospital, Capital Medical University, Beijing, 100069, China.|Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, China.
authors.forename: Xiang-Jun
authors.initials: XJ
authors.lastname: Zeng
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an, 710061, China.
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Kang
authors.affiliation: 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.|Department of Cardiology, Chaoyang Hospital, Capital Medical University, Beijing, 100069, China.|Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.affiliation: 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. hhli1995@yahoo.com.|Department of Cardiology, Chaoyang Hospital, Capital Medical University, Beijing, 100069, China. hhli1995@yahoo.com.|Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, China. hhli1995@yahoo.com.
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Li
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic; D017209:Apoptosis / Q000235:genetics; D001731:Bisphosphoglycerate Mutase / Q000235:genetics / Q000378:metabolism; D009202:Cardiomyopathies / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004317:Doxorubicin; D004734:Energy Metabolism / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects*; D053263:Gene Regulatory Networks / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D001731:Bisphosphoglycerate Mutase; D005947:Glucose
keywords: Apoptosis; Bpgm; Cardiomyopathy; Doxorubicin; Glucose metabolism; Microarray