An Engineered Bivalent Neuregulin Protects Against Doxorubicin-Induced Cardiotoxicity With Reduced Proneoplastic Potential
Name
Griffith_An engineered.pdf
Size
2.2 MB
Format
Adobe PDF
Checksum (MD5)
d6190090dd5b3f0e740af08863736b5a
Author(s)
Jay, Steven M.
Murthy, Ashwin C.
Hawkins, Jessica F.
Wortzel, Joshua R.
Steinhauser, Matthew L.
Alvarez, Luis M.
Gannon, Joseph
Macrae, Calum A.
Griffith, Linda G.
Lee, Richard T.
Date Issued
June 2013
Journal
Circulation
Publisher
American Heart Association
Citation
Jay, S. M., A. C. Murthy, J. F. Hawkins, J. R. Wortzel, M. L. Steinhauser, L. M. Alvarez, J. Gannon, C. A. Macrae, L. G. Griffith, and R. T. Lee. “An Engineered Bivalent Neuregulin Protects Against Doxorubicin-Induced Cardiotoxicity With Reduced Proneoplastic Potential.” Circulation 128, no. 2 (June 11, 2013): 152–161.
Version
Author's final manuscript
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Center for Gynepathology Research
Massachusetts Institute of Technology. Department of Biological Engineering
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1161/CIRCULATIONAHA.113.002203
