Neuregulin (NRG) growth factors through cognate tyrosine kinase receptors erbB2/erbB4 are required for the prevention of dilated cardiomyopathies. Combined therapy with antibodies blocking NRG signaling and anthracycline derivatives produces objective tumor regressions. However, the combined treatment displays an undesired effect by increasing the incidence of a severe cardiomyopathy in 30% of patients.
Our laboratory demonstrated that ventricular-specific erbB4 deletion (erbB4-KO) lead to dilated cardiomyopathy in adult mice. We aimed to investigate the molecular modifications underlying the synergistic cardiotoxicity of anthracycline derivatives together with the substantial blockade of the NRG pathway. The treatment of erbB4-KO mouse with doxorubicin (15 mg/kg, administered within a week) (erbB4-KOD) induces ventricular dilation with increased expression of fetal cardiac genes. Our laboratory demonstrated that both erbB2 and erbB4 protein accumulate in the T-tubules and doxorubicin treatment generated a dislocation of membrane s proteins. Therefore, we analyzed ventricular protein extracts by bidimensional electrophoresis (2D PAGE), protein phosphorylation and further mass spectrometry on peptide digest to identify modified proteins in the erbB4-KOD compared to KO. Our comparative analysis of proteins in erbB4-KOD versus WT,WTD, and erbB4-KO revealed differences in protein content and/or in the phosphorylation level of mitochondrial proteins.
