Acute doxorubicin cardiotoxicity is associated with miR-146a-induced inhibition of the neuregulin-ErbB pathway.
OBJECTIVE
A significant increase in congestive heart failure (CHF) was reported when the anti-ErbB2 antibody trastuzumab was used in combination with the chemotherapy drug doxorubicin (Dox). The aim of the present study was to investigate the role(s) of miRNAs in acute Dox-induced cardiotoxicity.


RESULTS
Neuregulin-1-ErbB signalling is essential for maintaining adult cardiac function. We found a significant reduction in ErbB4 expression in the hearts of mice after Dox treatment. Because the proteasome pathway was only partially involved in the reduction of ErbB4 expression, we examined the involvement of microRNAs (miRs) in the reduction of ErbB4 expression. miR-146a was shown to be up-regulated by Dox in neonatal rat cardiac myocytes. Using a luciferase reporter assay and overexpression of miR-146a, we confirmed that miR-146a targets the ErbB4 3'UTR. After Dox treatment, overexpression of miR-146a, as well as that of siRNA against ErbB4, induced cell death in cardiomyocytes. Re-expression of ErbB4 in miR-146a-overexpressing cardiomyocytes ameliorated Dox-induced cell death. To examine the loss of miR-146a function, we constructed 'decoy' genes that had tandem complementary sequences for miR-146a in the 3'UTR of a luciferase gene. When miR-146a 'decoy' genes were introduced into cardiomyocytes, ErbB4 expression was up-regulated and Dox-induced cell death was reduced.


CONCLUSIONS
These findings suggested that the up-regulation of miR-146a after Dox treatment is involved in acute Dox-induced cardiotoxicity by targeting ErbB4. Inhibition of both ErbB2 and ErbB4 signalling may be one of the reasons why those patients who receive concurrent therapy with Dox and trastuzumab suffer from CHF.
Horie
Takahiro
T
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
Ono
Koh
K
Nishi
Hitoo
H
Nagao
Kazuya
K
Kinoshita
Minako
M
Watanabe
Shin
S
Kuwabara
Yasuhide
Y
Nakashima
Yasuhiro
Y
Takanabe-Mori
Rieko
R
Nishi
Eiichiro
E
Hasegawa
Koji
K
Kita
Toru
T
Kimura
Takeshi
T
D020413:3' Untranslated Regions; D000818:Animals; D017209:Apoptosis; D009202:Cardiomyopathies / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D009154:Mutation; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020880:Neuregulins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D066247:Receptor, ErbB-4; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
D020413:3' Untranslated Regions; C554180:MIRN146 microRNA, rat; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D020880:Neuregulins; D004317:Doxorubicin; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4; D046988:Proteasome Endopeptidase Complex