Rol del receptor tirosina quinasa erbB2 en la cardiomiopatía hipertrófica dilatada.

BONANNO, MARINA; RIZZO, AGUSTÍN; GARCÍA RIVELLO, HERNÁN; CARY, LAI; HERTIG, CECILIA

Buenos Aires

Congreso; SAIB; 2015

Sociedad Argentina de Investigación Bioquímica y Biología Molecular

Neuregulin-1 (NRG1) signaling through tyrosine kinase receptors erbB2 and erbB4 is required for cardiac morphogenesis, and plays an essential role in maintaining the myocardial architecture during adulthood. Targeted immunotherapies blocking the survival of erbB2+ cancer cells revealed that an impaired NRG1 signal combined to anthracycline chemotherapy may lead to dilated cardiomyopathy in a subpopulation of treated patients. The ventricular-specific deletion of Erbb4 (erbB4-KO) manifested dilated cardiomyopathy, aggravated by the administration of anthracyclines (doxorubicin). The exacerbated toxicity, in the combined treatment, induced genes of the ubiquitin-proteasome system and autophagy.Myofibril proteins were largely ubiquitinated with the commonality of a subgroup of proteins in the erbB4- KO and the doxorubicin mice. We aimed to investigate the activities underlying cardiomyocyte damage and moreover, to evaluate the therapeutic effect of recombinant NRG1β peptides. We first examined biomarkers of apoptosis and autophagy (e.g. active caspase3, p62 and LC3II/I), then characterized the ubiquitination profile of myofibrils in 2D gels towards the monitoring of the rNRG1β effect through the reversion of the molecular modifications observed in cardiotoxic conditions. We have identified new consistent biomarkers of pathology and conclude that rNRG1β protects from cardiotoxic injury.