Acute Doxorubicin Cardiotoxicity is Associated with MiR-146a-induced Inhibition of the Neuregulin-ErbB Pathway

Overview

Journal Cardiovasc Res

Specialty Cardiology & Vascular Diseases

Date 2010 May 25

PMID 20495188

Citations 106

Authors

Takahiro Horie

Koh Ono

Hitoo Nishi

Kazuya Nagao

Minako Kinoshita

Shin Watanabe

Yasuhide Kuwabara

Yasuhiro Nakashima

Rieko Takanabe-Mori

Eiichiro Nishi

Koji Hasegawa

Toru Kita

Takeshi Kimura

Affiliations

Soon will be listed here.

Abstract

Aims: 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.

Methods And 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.

Conclusion: 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.

Citing Articles

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The Role of MicroRNAs in the Pathogenesis of Doxorubicin-Induced Vascular Remodeling.

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Dehydroevodiamine Alleviates Doxorubicin-Induced Cardiomyocyte Injury by Regulating Neuregulin-1/ErbB Signaling.

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MicroRNA-146: Biomarker and Mediator of Cardiovascular Disease.

Mahdavi F, Mardi S, Mohammadi S, Ansari S, Yaslianifard S, Fallah P Dis Markers. 2024; 2022:7767598.

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