Doxorubicin Exacerbates Membrane Modifications in erbB4 knockout Murine Model

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

Villa Carlos Paz, Córdoba

Congreso; XLIV Reunión Anual SAIB; 2008

Sociedad Argentina de Inveestigaciones en Bioquímica y Biología Molecular

Neuregulin (NRG) signaling through receptor tyrosine kinase erbB2 and erbB4 heterodimers is critical for the maintenance of adult heart function. Combined therapy of blocking antibodies of NRG signaling and anthracycline derivatives, inhibitors of mammary tumor growth, could lead to a severe cardiomyopathy.  We investigated the molecular consequences of an exacerbated cardiotoxicity in the ventricular muscle specific erbB4 knockout mouse by the injection of doxorubicin (5mg/kg x 3 within a week). In this setting, there are significant changes in the expression of growth factors involved in cardiac growth and of signals involved in stress and inflammatory process. One early event is the remarkable dilation of T-tubule membrane system. We first examined gene products that localized to the membrane as monitored by immunohistochemitry and western bots. A group of membrane proteins involved in cytoskeletal pathways were found reduced in 50% (ZO-1, Desmin, erB2) and /or delocalized from to Z-line and intercalated disc compared relative to unchanged Cx43 at the Gap junctions and compared to Wt mouse. These study was extended to a larger analysis of affected proteins by employing a proteomic approach. The identity of the membrane molecular modifications may reveal underlying mechanisms of the aggravated myopathy.