Recombinant human interleukin-1 receptor antagonist protects mice against acute doxorubicin-induced cardiotoxicity.
Doxorubicin is a potent anticancer drug which is widely used in the treatments of a variety of solid and hematopoietic tumors, but its use is limited by its cardiotoxicity and dose-dependent congestive heart failure. After finding a close connection between Interleukin-1 family and doxorubicin-induced cardiotoxicity, we assumed that recombinant human interleukin-1 receptor antagonist (rhIL-1Ra), the natural antagonist of interleukin-1, might have a protective role in doxorubicin-induced cardiotoxicity. In this report, Balb/c mice were intraperitoneally injected with doxorubicin (18 mg/kg) followed by injections of 1mg/kg rhIL-1Ra 4h later, and consecutive daily injections of rhIL-1Ra on the following 4 days (1mg/kg/day). We found that rhIL-1Ra significantly decreased malondialdehyde in cardiac tissue and prevented doxorubicin-associated cardiac troponin I elevations in serum, especially at day 14 after doxorubicin treatment. Importantly, rhIL-1Ra diminished doxorubicin-induced microstructural damages of cardiac tissue and rescued doxorubicin-caused reduction of cardiac functions exemplified by ejection fraction and fraction shortening. Our results reveal a potential role of rhIL-1Ra in protecting mice against doxorubicin-induced cardiac injuries and lead to a conclusion that this protein may be a potential candidate agent that inhibits cardiomyocyte-toxicity in doxorubicin-exposed patients.
Zhu
Jinzhou
J
Department of Cardiology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Zhang
Jing
J
Xiang
Di
D
Zhang
Zhonghui
Z
Zhang
Lin
L
Wu
Mingyuan
M
Zhu
Shunying
S
Zhang
Ruiyan
R
Han
Wei
W
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D004317:Doxorubicin / Q000633:toxicity*; D005260:Female; D006333:Heart Failure / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D053583:Interleukin-1beta / Q000097:blood; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D013318:Stroke Volume / Q000187:drug effects; D019210:Troponin I / Q000097:blood
D000970:Antineoplastic Agents; D002316:Cardiotonic Agents; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D053583:Interleukin-1beta; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D019210:Troponin I; D004317:Doxorubicin