DOXORUBICIN EXACERBATES MEMBRANE MODIFICATIONS IN ERBB4 KNOCKOUT MURINE MODEL

SÁNCHEZ JOVIC AE; VASTIC; CAVALLERO S; LISI C; MAZZELLA A; HERTIG CM

Cordoba , Argentina

Congreso; SAIB; 2008

Neuregulin (NRG) signaling through tyrosine kinase receptors erbB2 and erbB4 is critical for the maintenance of adult heart function. Combined therapy for breast tumors with antibodies blocking NRG signaling and anthracycline derivatives, may lead to a severe cardiomyopathy. We investigated the molecular consequences of an exacerbated cardiotoxicity in the ventricular muscle specific erbB4 KO mouse by the injection of doxorubicin (5 mg/kg, 3 times within a week). In this setting, there are significant changes in the expression of growth factors and of signals involved in stress and inflammatory process. One early event is a remarkable dilation of T-tubule membrane system. We therefore investigated molecules synergistically affected at the membrane and T-tubule structure. A group of membrane proteins involved in cytoskeletal pathways (ZO-1, desmin, erbB2) was found reduced in 50% relative to unchanged connexin-43 at the gap junctions and/or delocalized from Z-line and intercalated discs compared to Wt and KO mouse. A broader protein analysis is performed by employing a proteomic approach, initiated by a bidimensional protein separation (2D-PAGE) from membrane extracts. The identity of modified membrane components may reveal relevant underlying mechanisms of the aggravated myopathy.