Vasti Cecilia, Witt Henning, Said Matilde, Sorroche Patricia, García-Rivello Hernán, Ruiz-Noppinger Patricia, Hertig Cecilia M
Instituto de Investigaciones en Ingeniería Genética y Biología Molecular-(INGEBI), Vuelta de Obligado 2490, Buenos Aires 1428, Argentina.
ISRN Cardiol. 2012;2012:745185. doi: 10.5402/2012/745185. Epub 2012 Aug 29.
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.
越来越多的证据表明神经调节蛋白-1信号在成体心脏中起着至关重要的作用，此外，还表明神经调节蛋白信号受损会加剧阿霉素介导的心脏毒性。尽管有这些确凿的数据，但活性erbB2/erbB4异二聚体的特定心肌细胞靶点仍不清楚。在本文中，我们研究了在心室肌特异性erbB4基因敲除小鼠中，由于心脏对蒽环类药物毒性敏感而导致心肌细胞损伤所涉及的途径。我们进行了形态学分析以评估心室重构，并采用cDNA微阵列来评估特征性基因表达谱，通过实时RT-PCR验证数据，然后将其归类为功能类别和途径。我们证实了与肥厚反应经典特征相关基因的上调，这意味着在阿霉素处理的erbB4基因敲除心脏中存在erbB2依赖性机制。我们的结果表明IGF-I/PI-3'激酶途径显著下调，并通过揭示导致心肌细胞自噬空泡化的泛素-蛋白酶体系统改变，扩展了我们目前的认识。
