title: A mutually beneficial relationship between hepatocytes and cardiomyocytes mitigates doxorubicin-induced toxicity.
abstract: Use of doxorubicin (DOX) is limited by its toxicity in multiple organs. However, the relationship between different organs in response to DOX-induced injury is not well understood. We found that partial hepatectomy correlated with increased DOX-induced heart injury in vivo while supernatant prepared from DOX-treated hepatocytes mitigated DOX-induced cytotoxicity of cardiomyocytes in vitro. Meanwhile, the supernatant of DOX-treated cardiomyocytes mitigated DOX-induced cytotoxicity of hepatocytes. Investigation of the molecular mechanisms underlying these effects found that interleukin 6 (IL-6) was significantly up-regulated in DOX-treated tissues and cells, and supernatant from IL-6 treated cells had a similar effect to that from DOX-treated cells. Although the concentration of secreted IL-6 in supernatant from DOX-treated cells did not significantly differ, blockade of IL-6 signaling, by overexpressing SOCS3, suppressed expression of the downstream molecules trefoil factor family 3 (TFF3) and hepatocyte growth factor (HGF), impaired the mutually beneficial relationship between hepatocytes and cardiomyocytes. In conclusion, our study shows that a mutually beneficial relationship exists between hepatocytes and cardiomyocytes during the acute injury induced by DOX. Moreover, it demonstrates that this phenomenon may be indirectly caused by increased IL-6 expression and the activation of the downstream molecular mediators TFF3 and HGF in hepatocytes and cardiomyocytes, respectively.
authors.affiliation: Department of Biochemistry and Molecular Biology, Basic Medical Science College, Harbin Medical University, Harbin 150081, China.
authors.forename: Weiguang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing 312000, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Biochemistry and Molecular Biology, Basic Medical Science College, Harbin Medical University, Harbin 150081, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Dong
authors.affiliation: Department of Biochemistry and Molecular Biology, Basic Medical Science College, Harbin Medical University, Harbin 150081, China.
authors.forename: Handong
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, Basic Medical Science College, Harbin Medical University, Harbin 150081, China.
authors.forename: Fenglan
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Basic Medical Science College, Harbin Medical University, Harbin 150081, China. Electronic address: lihui@ems.hrbmu.edu.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004317:Doxorubicin / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D022781:Hepatocytes / Q000502:physiology*; D015848:Interleukin-5 / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D010957:Plasmids; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D000071165:Trefoil Factor-3
chemical_list: D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; D015848:Interleukin-5; D009479:Neuropeptides; C099037:TFF3 protein, rat; D000071165:Trefoil Factor-3; D012313:RNA; D017228:Hepatocyte Growth Factor; D004317:Doxorubicin
keywords: Cardiotoxicity; Doxorubicin; Hepatotoxicity; Interleukin 6; Mutually beneficial relationship