An engineered bivalent neuregulin protects against doxorubicin-induced cardiotoxicity with reduced proneoplastic potential.

TitleAn engineered bivalent neuregulin protects against doxorubicin-induced cardiotoxicity with reduced proneoplastic potential.
Publication TypeJournal Article
Year of Publication2013
AuthorsJay, SM, Murthy, AC, Hawkins, JF, Wortzel, JR, Steinhauser, ML, Alvarez, LM, Gannon, J, Macrae, CA, Griffith, LG, Lee, RT
Date Published2013 Jul 9
KeywordsAmino Acid Sequence, Animals, Animals, Newborn, Cardiotonic Agents, Cardiotoxins, Cell Line, Tumor, Cell Survival, Chemical Engineering, Doxorubicin, Female, Humans, Male, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Myocytes, Cardiac, Neuregulin-1, Random Allocation, Rats, Single-Blind Method

BACKGROUND: Doxorubicin (DOXO) is an effective anthracycline chemotherapeutic, but its use is limited by cumulative dose-dependent cardiotoxicity. Neuregulin-1β is an ErbB receptor family ligand that is effective against DOXO-induced cardiomyopathy in experimental models but is also proneoplastic. We previously showed that an engineered bivalent neuregulin-1β (NN) has reduced proneoplastic potential in comparison with the epidermal growth factor-like domain of neuregulin-1β (NRG), an effect mediated by receptor biasing toward ErbB3 homotypic interactions uncommonly formed by native neuregulin-1β. Here, we hypothesized that a newly formulated, covalent NN would be cardioprotective with reduced proneoplastic effects in comparison with NRG.METHODS AND RESULTS: NN was expressed as a maltose-binding protein fusion in Escherichia coli. As established previously, NN stimulated antineoplastic or cytostatic signaling and phenotype in cancer cells, whereas NRG stimulated proneoplastic signaling and phenotype. In neonatal rat cardiomyocytes, NN and NRG induced similar downstream signaling. NN, like NRG, attenuated the double-stranded DNA breaks associated with DOXO exposure in neonatal rat cardiomyocytes and human cardiomyocytes derived from induced pluripotent stem cells. NN treatment significantly attenuated DOXO-induced decrease in fractional shortening as measured by blinded echocardiography in mice in a chronic cardiomyopathy model (57.7±0.6% versus 50.9±2.6%, P=0.004), whereas native NRG had no significant effect (49.4±3.7% versus 50.9±2.6%, P=0.813).CONCLUSIONS: NN is a cardioprotective agent that promotes cardiomyocyte survival and improves cardiac function in DOXO-induced cardiotoxicity. Given the reduced proneoplastic potential of NN versus NRG, NN has translational potential for cardioprotection in patients with cancer receiving anthracyclines.

Alternate JournalCirculation
PubMed ID23757312
PubMed Central IDPMC3753575
Grant ListAG032977 / AG / NIA NIH HHS / United States
DE019523 / DE / NIDCR NIH HHS / United States
DK090147 / DK / NIDDK NIH HHS / United States
EB003805 / EB / NIBIB NIH HHS / United States
HL112905 / HL / NHLBI NIH HHS / United States
K99 HL112905 / HL / NHLBI NIH HHS / United States
R00 HL112905 / HL / NHLBI NIH HHS / United States
R01 AG032977 / AG / NIA NIH HHS / United States
U54-CA112967 / CA / NCI NIH HHS / United States