Program

PO1-2-30

Therapeutic effects of ghrelin and des-acyl ghrelin on anthracycline doxorubicin-induced cardiac toxicit

[Speaker] Miki Nonaka:1
[Co-author] Nagomi Kurebayashi:2, Takashi Murayama:2, Masami Sugihara:3, Hiroshi Hosoda:4, Shosei Kishida:5, Miaki Uzu:1, Kenji Kangawa:6, Takashi Sakurai:2, Yasuhito Uezono:1,7
1:Division of Cancer Pathophysiology, National Cancer Center Research Institute, Japan, 2:Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Japan, 3:Department of Clinical Laboratory Medicine, Juntendo University School of Medicine, Japan, 4:Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Research Institute, Japan, 5:Department of Biochemistry and Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, Japan, 6:National Cerebral and Cardiovascular Center Research Institute, Japan, 7:Division of Supportive Care Research, National Cancer Center, Exploratory Oncology Research & Clinical Trial Center, Japan

[Background]
 Anthracycline doxorubicin (DOX), which has been used for cancer chemotherapy, often causes cardiotoxicity. Recent reports indicate that orexigenic hormone ghrelin and des-acyl ghrelin, which is a non-octanoylated form of ghrelin, inhibit DOX-induced cardiotoxicity. However, molecular mechanisms of ghrelin and des-acyl ghrelin remain unclear. In the present study, to provide mechanistic experimental evidence of these peptides against DOX-induced cardiotoxicity, we examined the effects of ghrelin and des-acyl ghrelin on cell damage, cell death, apoptosis, and cardiac dysfunction using an in vitro and in vivo system.
[Methods and Results]
 Effects of ghrelin and des-acyl ghrelin were evaluated using H9C2 cardiomyocytes. H9C2 cells were treated with DOX (0-1 μM) for 72h with or without ghrelin or des-acyl ghrelin (1 μM each). Ghrelin and des-acyl ghrelin significantly reduced the DOX-induced cell damage and cell death, with greater effects at des-acyl ghrelin. In addition, ghrelin and des-acyl ghrelin prevented cell damage and cell death through apoptosis, and des-acyl ghrelin but not ghrelin significantly decreased ROS generation. In in vivo experiment, DOX was administered once at a dose of 15 mg/kg to 8 weeks old male C57BL/6 mice intraperitoneally. At 1 day before DOX treatment, we started subcutaneous administration to mice twice daily with des-acyl ghrelin (100 mg/kg) for 8 consecutive days. Treatment with DOX in mice caused left ventricular systolic dysfunction. On the other hand, mice treated with DOX with des-acyl ghrelin significantly improved systolic dysfunction. In addition, non-phosphorylated Cx43 was increased in the mice treated with DOX alone, and DOX with des-acyl ghrelin treated mice were markedly decreased expression levels of non-phosphorylated Cx43. These results suggest that des-acyl ghrelin prevented the progression in left ventricular ejection fraction decrease in DOX-treated mice probably because of the decrease expression levels of non-phosphorylated Cx43.
[Conclusions]
 Our study showed that ghrelin and des-acyl ghrelin may have therapeutic effects in DOX-induced cardiotoxicity. Further, des-acyl ghrelin may have greater beneficial effects for the reduction of cellular ROS generation and expression level of non-phosphorylated Cx43. Further studies are required to clarify the mechanisms how des-acyl ghrelin prevents the DOX-induced cardiotoxicity and such experiments are underway.

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