Abstract
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.
Highlights
Overexpression of erbB2 oncogene in breast cancer cells is indicative of highly proliferative tumors with a poor prognosis following conventional chemotherapy [1]
Our results indicate the remarkable downregulation of insulin-like growth factor-I (IGF-I)/PI-3 kinase pathway and extends our current knowledge by uncovering an altered ubiquitin-proteasome system leading to cardiomyocyte autophagic vacuolization
Both wildtype (WT) and erbB4KO mice were treated with doxorubicin (15 mg/kg), subsequently named WTD and KOD, respectively
Summary
Overexpression of erbB2 oncogene in breast cancer cells is indicative of highly proliferative tumors with a poor prognosis following conventional chemotherapy [1]. Combined therapy of anthracycline derivatives and antibodies against erbB2 (i.e., trastuzumab, Herceptin) is clinically effective with objective tumor regressions and lower rates of both recurrence and mortality of breast cancer patients relatively resistant to tamoxifen [2, 3]. The synergistic cardiotoxicity of the combined therapy results in a 30% incidence of cardiac dilation compared to the 1–5% registered in patients receiving either trastuzumab or anthrayclines alone. Long-term retrospective analyses of trastuzumab suggest that an impaired neuregulin-1 (NRG-1) signaling sensitizes the heart towards a toxic response, that is, to anthracycline derivatives [3]. Murine models harboring mutations in any component of the NRG-1 signaling through tyrosine kinase receptors erbB2 and erbB4 have demonstrated that this pathway is critical for cardiac development and the maintenance of proper adult heart remodeling and function. Despite the evidence on the essential role of NRG1 signaling in the adult heart, the specific cardiomyocyte targets of the active erbB2/erbB4 heterodimer remain unknown
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