Glial Growth Factor 2 protects doxorubicin exposed cardiomyocytes through BAD/Bcl-2 pathway activation

Abstract

Neuregulin/erbB signalling is cardioprotective as seen in models of cardiotoxicity associated with the use of chemotherapeutics. Our studies reveal a function of Bcl-2 to protect cardiomyocytes concomitant with GGF2-induced increases in levels of phospho-BAD (pBAD) along with activation of PI3 kinase (PI3K) and MAP kinase (MAPK). We show that phosphorylation of BAD is dependent upon GGF2 mediated activation of PI3K. In addition, examination of mitochondrial gene expression shows several members of the Bcl-2 family are down-regulated by doxorubicin, while GGF2 is able to reverse this effect. While many in vitro model systems of doxorubicin cardiotoxicity have observed PI3K-dependent cytoprotective effects of neuregulin's, the present results demonstrate that GGF2 mediates cytoprotective actions in HL-1 cardiomyocytes through regulation of mitochondrial mediated apoptosis via the PI3K/Bcl-2 pathway.