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Inducible and Reversible Dominant-negative (DN) Protein Inhibition
Published on: January 7, 2019
Doxorubicin and NRG-1/erbB4-Deficiency Affect Gene Expression Profile: Involving Protein Homeostasis in Mouse
Cecilia Vasti1, Henning Witt, Matilde Said
1Instituto de Investigaciones en Ingeniería Genética y Biología Molecular-(INGEBI), Vuelta de Obligado 2490, Buenos Aires 1428, Argentina.
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.
Insights
Neuregulin-1 signaling is crucial for adult heart function and protects against doxorubicin toxicity. Impaired signaling in erbB4 knockout mice reveals new pathways contributing to heart damage.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Neuregulin-1 (NRG1) signaling plays a vital role in adult heart physiology.
- Impaired NRG1 signaling exacerbates doxorubicin-induced cardiotoxicity.
- The specific cardiomyocyte targets of the erbB2/erbB4 heterodimer remain elusive.
Purpose of the Study:
- To investigate pathways involved in cardiomyocyte damage in the context of anthracycline toxicity.
- To examine cardiac sensitization to doxorubicin in ventricular muscle-specific erbB4 knockout mice.
Main Methods:
- Morphological analyses for ventricular remodeling assessment.
- cDNA microarray for gene expression profiling.
- Real-time RT-PCR for data verification and pathway analysis.
Main Results:
- Confirmed upregulation of genes associated with hypertrophic response in erbB4-KO hearts, suggesting an erbB2-dependent mechanism.
- Observed significant downregulation of the IGF-I/PI-3' kinase pathway.
- Uncovered an altered ubiquitin-proteasome system leading to cardiomyocyte autophagic vacuolization.
Conclusions:
- The study elucidates novel molecular pathways contributing to doxorubicin cardiotoxicity in the absence of functional erbB4.
- Findings highlight the complex interplay between NRG1 signaling, hypertrophy, and cellular degradation pathways in the heart.