Doxorubicin and NRG-1-erbB4-Deficiency Affect Gene Expression Profile: Involving Protein Homeostasis in MouseReport as inadecuate

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ISRN CardiologyVolume 2012 2012, Article ID 745185, 11 pages

Research Article

Instituto de Investigaciones en Ingeniería Genética y Biología Molecular—INGEBI, Vuelta de Obligado 2490, Buenos Aires 1428, Argentina

Center for Cardiovascular Research, Charité Universitätsmedizin Berlin, Hessische Strasse 3-4, 10115 Berlin, Germany

Centro de Investigaciones Cardiovasculares, Facultad de Medicina, Universidad de La Plata, Diagonal 120 y Av. 60, 1900 La Plata, Argentina

Hospital Italiano Buenos Aires, Servicio de Anatomía Patológica y Laboratorio, Gascón 450, 1181 Buenos Aires, Argentina

Received 16 April 2012; Accepted 1 July 2012

Academic Editors: G. Moe and T. Shioi

Copyright © 2012 Cecilia Vasti et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


The accumulating evidence demonstrates the essential role of neuregulin-1 signaling in the adult heart, and, moreover, indicates that an impaired neuregulin signaling exacerbates the doxorubicin-mediated cardiac toxicity. Despite this strong data, the specific cardiomyocyte targets of the active erbB2-erbB4 heterodimer remain unknown. In this paper, we examined pathways involved in cardiomyocyte damage as a result of the cardiac sensitization to anthracycline toxicity in the ventricular muscle-specific erbB4 knockout mouse. We performed morphological analyses to evaluate the ventricular remodeling and employed a cDNA microarray to assess the characteristic gene expression profile, verified data by real-time RT-PCR, and then grouped into functional categories and pathways. We confirm the upregulation of genes related to the classical signature of a hypertrophic response, implicating an erbB2-dependent mechanism in doxorubicin-treated erbB4-KO hearts. Our results indicate the remarkable downregulation of IGF-I-PI-3′ kinase pathway and extends our current knowledge by uncovering an altered ubiquitin-proteasome system leading to cardiomyocyte autophagic vacuolization.

Author: Cecilia Vasti, Henning Witt, Matilde Said, Patricia Sorroche, Hernán García-Rivello, Patricia Ruiz-Noppinger, and Cecilia



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