Enhanced-autophagy by exenatide mitigates doxorubicin-induced cardiotoxicity.
OBJECTIVE
Exenatide is a glucagon-like peptide-1 analogue that mitigates myocardial injury caused by ischemia-reperfusion injury via the survival signaling pathway. We hypothesized that exenatide would provide a protective effect in doxorubicin-induced cardiotoxicity.


METHODS
H9c2 cardiomyocytes were pre-treated with exenatide followed by doxorubicin (DOX), and cell viability and intracellular reactive oxygen species (ROS) were subsequently measured. In order to determine the role of autophagy, we performed western blot as well as TUNEL and autophagosome staining. Additionally, rats were treated with exenatide 1h prior to every DOX treatment. Left ventricular (LV) function and performance were then assessed by echocardiography. Myocardial and serum ROS was measured with DHE fluorescence and ROS/RNS assay.


RESULTS
DOX-induced caspase-3 activation decreased after pre-treatment with exenatide both in vivo and in vitro. Oxidative stress was attenuated by exenatide in H9c2 cells, as well as in cardiac tissue and serum. The number of autophagosomes and autophagic markers were further increased by exenatide in the DOX-treated H9c2 cells, which mediated AMPK activation. Suppression of the autophagosome abolished exenatide-induced anti-apoptotic effect. Echocardiography showed that pre-treatment with exenatide significantly improved LV dysfunction that is induced by DOX treatment. Exenatide inhibits the DOX-induced production of intracellular ROS and apoptosis in the myocardium. The autophagic markers increased in exenatide pre-treated cardiac tissue.


CONCLUSIONS
Exenatide reduces DOX-induced apoptosis of cardiomyocytes by upregulating autophagy and improving cardiac dysfunction. These novel results highlight the therapeutic potential of exenatide to prevent doxorubicin cardiotoxicity.
Division of Cardiology, Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University, Seoul, Republic of Korea.
Kyung Hye
KH
Lee
Division of Cardiology, Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University, Seoul, Republic of Korea.
Haneul
H
Cho
Division of Cardiology, Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University, Seoul, Republic of Korea.
Sora
S
Lee
Division of Cardiology, Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University, Seoul, Republic of Korea.
Jong Shin
JS
Woo
Division of Cardiology, Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University, Seoul, Republic of Korea.
Byung Hyun
BH
Cho
Division of Cardiology, Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University, Seoul, Republic of Korea.
Jung Hee
JH
Kang
Division of Cardiology, Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University, Seoul, Republic of Korea.
Yun-Mi
YM
Jeong
Division of Cardiology, Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University, Seoul, Republic of Korea.
Xian Wu
XW
Cheng
Division of Cardiology, Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University, Seoul, Republic of Korea. Electronic address: mylovekw@hanmail.net.
Weon
W
Kim
D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D015153:Blotting, Western; D066126:Cardiotoxicity / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002460:Cell Line; D002470:Cell Survival; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity; D004452:Echocardiography; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000503:physiopathology*; D020287:In Situ Nick-End Labeling; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D016277:Ventricular Function, Left
D017382:Reactive Oxygen Species; D004317:Doxorubicin
Cardiotoxicity; Doxorubicin; Glucagon-like peptide-1 analogue; Prevention