Hai Ying Fu1, Shoji Sanada1, Takashi Matsuzaki1, Yulin Liao1, Keiji Okuda1, Masaki Yamato1, Shota Tsuchida1, Ryo Araki1, Yoshihiro Asano1, Hiroshi Asanuma1, Masanori Asakura1, Brent A French1, Yasushi Sakata1, Masafumi Kitakaze1, Tetsuo Minamino2. 1. 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.). 2. 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.
Abstract
RATIONALE: 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. METHODS AND 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.
RATIONALE: 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. METHODS AND 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: Francisca Schultz; Pamela Swiatlowska; Anita Alvarez-Laviada; Jose L Sanchez-Alonso; Qianqian Song; Antoine A F de Vries; Daniël A Pijnappels; Emily Ongstad; Vania M M Braga; Emilia Entcheva; Robert G Gourdie; Michele Miragoli; Julia Gorelik Journal: FASEB J Date: 2019-07-05 Impact factor: 5.191