In a mouse model, doxorubicin exacerbates cardiac toxicity in the setting of erbB4 deficiency by altering the ubiquitin-proteasome system and downregulating the IGF-I/PI-3' kinase pathway.
Suggests erbB4 modulates doxorubicin cardiotoxicity in mice; hypothesis-generating and leaves open human relevance.
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.
No takes yet. Share an insight, caveat, or question.
Vasti et al. (2012) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: