Objectives In previous studies, it has been shown that recombinant human neuregulin-1(rhNRG-1) is capable of improving the survival rate in animal models of doxorubicin (DOX)-induced cardiomyopathy; however, the underlying mechanism of this phenomenon remains unknown.
Methods In this study, the role of rhNRG-1 in attenuating doxorubicin-induce apoptosis is confirmed.Neonatal rat ventricular myocytes (NRVMs) were devided into six groups: control, DOX, rhNRG-1, LY294002, rhNRG-1 + DOX, rhNRG-1 + DOX + LY294002, in order to both induce apoptosis and determine the effects of rhNRG-1 on the process. Activation of apoptosis was determined by observing increases in the protein levels of classic apoptosis markers (including cleaved caspase-3, cytochrome c, Bcl-2, BAX by Western blot analysis and TdT-mediated Dutp-mediated Dutp nick-end labelling (TUNEL) staining). The activation of Akt was detected by means of Western blot analysis.
Results The study results showed that doxorubicin increased the number of TUNEL positive cells, as well as the protein levels of cleaved caspase-3 and cytochrome c, and reduced the ration of Bcl-2/Bax. However, all of these effects were markedly antagonised by pretreament with rhNRG-1. It was then further demonstrated that the effects of rhNRG-1 could be blocked by the phosphoinositole-3-kinase inhibitor LY294002, indicating the involvement of the Akt process in mediating the process.
Conclusions RhNRG-1 is a potent inhibitor of doxorubicin-induced apoptosis, which acts through the PI3K-Akt pathway. RhNRG-1 is a novel therapeutic drug which may be effective in preventing further damage from occurring in DOX-induced damaged myocardium.