title: Gene expression profiling identifies the novel role of immunoproteasome in doxorubicin-induced cardiotoxicity.
abstract: The most well-known cause of chemotherapy-induced cardiotoxicity is doxorubicin (DOX). The ubiquitin-proteasome system (UPS) is the main cellular machinery for protein degradation in eukaryotic cells. However, the expression pattern of the UPS in DOX-induced cardiotoxicity remains unclear. C57BL/6 mice were intraperitoneally injected with a single dose of DOX (15mg/kg). After 1, 3 and 5 days, cardiac function and apoptosis were detected with echocardiography and TUNEL assay. Microarray assay and qPCR analysis were also performed at day 5. We found that DOX caused a significant decrease in cardiac function at day 5 and increase in cardiomyocyte apoptosis at days 3 and 5. Microarray data revealed that totally 1185 genes were significantly regulated in DOX-treated heart, and genes involved in apoptosis and the UPS were mostly altered. Among them, the expression of 3 immunoproteasome catalytic subunits (β1i, β2i and β5i) was markedly down-regulated. Moreover, DOX significantly decreased proteasome activities and enhanced polyubiquitinated proteins in the heart. Importantly, overexpression of immunoproteasome catalytic subunits (β1i, β2i or β5i) significantly attenuated DOX-induced cardiomyocyte apoptosis and other UPS gene expression while knockdown of them significantly increased DOX-induced cardiomyocyte apoptosis. These effects were partially associated with increased degradation of multiple pro-apoptotic proteins. In conclusion, our studies suggest that immunoproteasome plays an important role in DOX-induced cardiomyocyte apoptosis, and may be a novel therapeutic target for prevention of DOX-induced cardiotoxicity.
authors.affiliation: Department of Physiology and Pathophysiology, Beijing Anzhen Hospital the Key Laboratory of Remodeling-Related Cardiovascular Diseases, School of Basic Medical Sciences, Capital Medical University, 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, School of Basic Medical Sciences, Capital Medical University, 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, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China. Electronic address: megan_zeng@163.com.
authors.forename: Xiang-Jun
authors.initials: XJ
authors.lastname: Zeng
authors.affiliation: Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
authors.forename: Yun-Long
authors.initials: YL
authors.lastname: Xia
authors.affiliation: Department of Physiology and Pathophysiology, Beijing Anzhen Hospital the Key Laboratory of Remodeling-Related Cardiovascular Diseases, School of Basic Medical Sciences, Capital Medical University, 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, School of Basic Medical Sciences, Capital Medical University, 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. Electronic address: hhli1995@yahoo.com.
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Li
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic; D017209:Apoptosis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004317:Doxorubicin; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D006331:Heart Diseases / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D054875:Ubiquitination
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; C569717:PSMB2 protein, mouse; D046988:Proteasome Endopeptidase Complex; C478802:Psmb5 protein, mouse
keywords: Apoptosis; Cardiotoxicity; Doxorubicin; Immunoproteasome; Microarray; Ubiquitin-proteasome system