ANTHRACYCLINE-MEDIATED CARDIOTOXICITY IN VENTRICULAR SPECIFIC ERBB4 KNOCKOUT MOUSE

MALVICINI M, BUITRAGO-EMANUEL E, CAVALLERO S, PAVETO C, HERTIG CM.

Misiones

Congreso; LV Reunion Anual de la Sociedad Argentina de Investigación Bioquimica; 2004

Sociedad Argentina de Investigación Bioquímica (SAIC)

An effective antibody-based therapy directed against erbB2 for the reduction of mammary tumors could lead to a severe cardiomyopathy when combined to anthracycline chemotherapy. We showed that conditional inactivation of erbB4 in ventricular muscle (erbB4 CKO) resulted in cardiac dilation, suggesting that Neuregulin signaling through erbB2 and erbB4 heterodimers may not only act as a modifier but as an essential component for normal cardiac remodeling. Although doxorubicin-mediated programmed cell death may induce cardiac dysfunction, the relative number of apoptotic cells was similar in wildtype and erbB4 CKO hearts as monitored by Tunel and Bax/Bcl-2 ratio. We therefore investigated possible targets for the potentiated cardiotoxicity in doxorubicininjected erbB4 CKO compared to wildtype mouse. We examined changes in the subcellular targeting and activity of related membrane proteins in tissue sections by immunohistochemistry and in cell extracts by Western blots. ErbB2 was found misslocalized with a 2-fold reduction in membrane extracts from doxorubicin-treated erbB4 CKO. The significant ß-adrenergic response indicates that the overall integrity of the membrane is not affected in the absence of erbB4. We suggest that erbB4 links neuregulin signaling to scaffold proteins involved in the regulation of the cardiomyocyte architecture and myocardial contractility.