title: Chemical Endoplasmic Reticulum Chaperone Alleviates Doxorubicin-Induced Cardiac Dysfunction.
abstract: BACKGROUND
  Doxorubicin is an effective chemotherapeutic agent for cancer, but its use is often limited by cardiotoxicity. Doxorubicin causes endoplasmic reticulum (ER) dilation in cardiomyocytes, and we have demonstrated that ER stress plays important roles in the pathophysiology of heart failure.
  
  
  OBJECTIVE
  We evaluated the role of ER stress in doxorubicin-induced cardiotoxicity and examined whether the chemical ER chaperone could prevent doxorubicin-induced cardiac dysfunction.
  
  
  RESULTS
  We confirmed that doxorubicin caused ER dilation in mouse hearts, indicating that doxorubicin may affect ER function. Doxorubicin activated an ER transmembrane stress sensor, activating transcription factor 6, in cultured cardiomyocytes and mouse hearts. However, doxorubicin suppressed the expression of genes downstream of activating transcription factor 6, including X-box binding protein 1. The decreased levels of X-box binding protein 1 resulted in a failure to induce the expression of the ER chaperone glucose-regulated protein 78 which plays a major role in adaptive responses to ER stress. In addition, doxorubicin activated caspase-12, an ER membrane-resident apoptotic molecule, which can lead to cardiomyocyte apoptosis and cardiac dysfunction. Cardiac-specific overexpression of glucose-regulated protein 78 by adeno-associated virus 9 or the administration of the chemical ER chaperone 4-phenylbutyrate attenuated caspase-12 cleavage, and alleviated cardiac apoptosis and dysfunction induced by doxorubicin.
  
  
  CONCLUSIONS
  Doxorubicin activated the ER stress-initiated apoptotic response without inducing the ER chaperone glucose-regulated protein 78, further augmenting ER stress in mouse hearts. Cardiac-specific overexpression of glucose-regulated protein 78 or the administration of the chemical ER chaperone alleviated the cardiac dysfunction induced by doxorubicin and may facilitate the safe use of doxorubicin for cancer treatment.
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (H.Y.F., S.S., T.M., K.O., M.Y., S.T., R.A., Y.A., Y.S., T.M.); Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China (Y.L.); Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan (H.A.); Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Osaka, Japan (M.A., M.K.); and Department of Biomedical Engineering, University of Virginia, Charlottesville (B.A.F.).
authors.forename: Hai Ying
authors.initials: HY
authors.lastname: Fu
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (H.Y.F., S.S., T.M., K.O., M.Y., S.T., R.A., Y.A., Y.S., T.M.); Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China (Y.L.); Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan (H.A.); Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Osaka, Japan (M.A., M.K.); and Department of Biomedical Engineering, University of Virginia, Charlottesville (B.A.F.).
authors.forename: Shoji
authors.initials: S
authors.lastname: Sanada
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (H.Y.F., S.S., T.M., K.O., M.Y., S.T., R.A., Y.A., Y.S., T.M.); Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China (Y.L.); Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan (H.A.); Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Osaka, Japan (M.A., M.K.); and Department of Biomedical Engineering, University of Virginia, Charlottesville (B.A.F.).
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuzaki
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (H.Y.F., S.S., T.M., K.O., M.Y., S.T., R.A., Y.A., Y.S., T.M.); Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China (Y.L.); Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan (H.A.); Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Osaka, Japan (M.A., M.K.); and Department of Biomedical Engineering, University of Virginia, Charlottesville (B.A.F.).
authors.forename: Yulin
authors.initials: Y
authors.lastname: Liao
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (H.Y.F., S.S., T.M., K.O., M.Y., S.T., R.A., Y.A., Y.S., T.M.); Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China (Y.L.); Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan (H.A.); Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Osaka, Japan (M.A., M.K.); and Department of Biomedical Engineering, University of Virginia, Charlottesville (B.A.F.).
authors.forename: Keiji
authors.initials: K
authors.lastname: Okuda
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (H.Y.F., S.S., T.M., K.O., M.Y., S.T., R.A., Y.A., Y.S., T.M.); Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China (Y.L.); Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan (H.A.); Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Osaka, Japan (M.A., M.K.); and Department of Biomedical Engineering, University of Virginia, Charlottesville (B.A.F.).
authors.forename: Masaki
authors.initials: M
authors.lastname: Yamato
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (H.Y.F., S.S., T.M., K.O., M.Y., S.T., R.A., Y.A., Y.S., T.M.); Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China (Y.L.); Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan (H.A.); Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Osaka, Japan (M.A., M.K.); and Department of Biomedical Engineering, University of Virginia, Charlottesville (B.A.F.).
authors.forename: Shota
authors.initials: S
authors.lastname: Tsuchida
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (H.Y.F., S.S., T.M., K.O., M.Y., S.T., R.A., Y.A., Y.S., T.M.); Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China (Y.L.); Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan (H.A.); Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Osaka, Japan (M.A., M.K.); and Department of Biomedical Engineering, University of Virginia, Charlottesville (B.A.F.).
authors.forename: Ryo
authors.initials: R
authors.lastname: Araki
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (H.Y.F., S.S., T.M., K.O., M.Y., S.T., R.A., Y.A., Y.S., T.M.); Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China (Y.L.); Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan (H.A.); Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Osaka, Japan (M.A., M.K.); and Department of Biomedical Engineering, University of Virginia, Charlottesville (B.A.F.).
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Asano
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (H.Y.F., S.S., T.M., K.O., M.Y., S.T., R.A., Y.A., Y.S., T.M.); Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China (Y.L.); Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan (H.A.); Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Osaka, Japan (M.A., M.K.); and Department of Biomedical Engineering, University of Virginia, Charlottesville (B.A.F.).
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asanuma
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (H.Y.F., S.S., T.M., K.O., M.Y., S.T., R.A., Y.A., Y.S., T.M.); Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China (Y.L.); Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan (H.A.); Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Osaka, Japan (M.A., M.K.); and Department of Biomedical Engineering, University of Virginia, Charlottesville (B.A.F.).
authors.forename: Masanori
authors.initials: M
authors.lastname: Asakura
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (H.Y.F., S.S., T.M., K.O., M.Y., S.T., R.A., Y.A., Y.S., T.M.); Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China (Y.L.); Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan (H.A.); Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Osaka, Japan (M.A., M.K.); and Department of Biomedical Engineering, University of Virginia, Charlottesville (B.A.F.).
authors.forename: Brent A
authors.initials: BA
authors.lastname: French
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (H.Y.F., S.S., T.M., K.O., M.Y., S.T., R.A., Y.A., Y.S., T.M.); Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China (Y.L.); Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan (H.A.); Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Osaka, Japan (M.A., M.K.); and Department of Biomedical Engineering, University of Virginia, Charlottesville (B.A.F.).
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakata
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (H.Y.F., S.S., T.M., K.O., M.Y., S.T., R.A., Y.A., Y.S., T.M.); Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China (Y.L.); Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan (H.A.); Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Osaka, Japan (M.A., M.K.); and Department of Biomedical Engineering, University of Virginia, Charlottesville (B.A.F.).
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.affiliation: From the Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (H.Y.F., S.S., T.M., K.O., M.Y., S.T., R.A., Y.A., Y.S., T.M.); Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China (Y.L.); Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan (H.A.); Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Osaka, Japan (M.A., M.K.); and Department of Biomedical Engineering, University of Virginia, Charlottesville (B.A.F.). minamino@cardiology.med.osaka-u.ac.jp.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Minamino
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D002478:Cells, Cultured; D004317:Doxorubicin / Q000633:toxicity*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D006333:Heart Failure / Q000139:chemically induced* / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010654:Phenylbutyrates / Q000627:therapeutic use; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid; D004317:Doxorubicin
keywords: apoptosis; cardiac dysfunction; doxorubicin; endoplasmic reticulum chaperone; endoplasmic reticulum stress