NEUREGULIN-1 ATTENUATES MYOCARDIAL INJURY IN ANTHRACYCLINEMEDIATED CARDIOTOXICITY IN MOUSE

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

Mar del Plata

Congreso; 51 Annual Meeting Argentine Society for Biochemistry and Molecular Biology; 2015

SAIB

Neuregulin-1 (NRG1) signaling through thetyrosine kinase receptors erbB2 and erbB4 is required for cardiacmorphogenesis, and plays an essential role in maintaining the myocardialarchitecture during adulthood. Targeted immunotherapies blocking the survivalof erbB2+ cancer cells revealed that an impaired NRG1 signal underanthracycline chemotherapy may lead to dilated cardiomyopathy in asubpopulation of treated patients. The ventricular-specific deletion of Erbb4(erbB4-KO) manifested dilated cardiomyopathy, aggravated by the administrationof anthracyclines (doxorubicin). The exacerbated toxicity, in the combinedtreatment, induced genes of the ubiquitin-proteasome system and autophagy.Myofibril proteins were largely ubiquitinated with the commonality of asubgroup of proteins in the erbB4-KO and the doxorubicin mice. We aimed toinvestigate the activities underlying cardiomyocyte damage and moreover, toevaluate the therapeutic effect of recombinant NRG1βpeptides. We first examined biomarkers of apoptosis and autophagy (e.g. activecaspase3, p62 and LC3II/I), then characterized the ubiquitination profile ofmyofibrils in 2D gels towards the monitoring of the rNRG1βeffect through the reversion of the molecular modifications observed incardiotoxic conditions. We have identified new consistent biomarkers ofpathology and conclude that rNRG1β protects from cardiotoxic injury.