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Activation of the MET receptor attenuates doxorubicin‐induced cardiotoxicity in vivo and in vitro

BACKGROUND AND PURPOSE: Doxorubicin anti‐cancer therapy is associated with cardiotoxicity, resulting from DNA damage response (DDR). Hepatocyte growth factor (HGF) protects cardiomyocytes from injury, but its effective use is compromised by low biodistribution. In this study, we have investigated wh...

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Autores principales: Gallo, Simona, Spilinga, Martina, Albano, Raffaella, Ferrauto, Giuseppe, Di Gregorio, Enza, Casanova, Elena, Balmativola, Davide, Bonzano, Alessandro, Boccaccio, Carla, Sapino, Anna, Comoglio, Paolo Maria, Crepaldi, Tiziana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280013/
https://www.ncbi.nlm.nih.gov/pubmed/32133617
http://dx.doi.org/10.1111/bph.15039
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author Gallo, Simona
Spilinga, Martina
Albano, Raffaella
Ferrauto, Giuseppe
Di Gregorio, Enza
Casanova, Elena
Balmativola, Davide
Bonzano, Alessandro
Boccaccio, Carla
Sapino, Anna
Comoglio, Paolo Maria
Crepaldi, Tiziana
author_facet Gallo, Simona
Spilinga, Martina
Albano, Raffaella
Ferrauto, Giuseppe
Di Gregorio, Enza
Casanova, Elena
Balmativola, Davide
Bonzano, Alessandro
Boccaccio, Carla
Sapino, Anna
Comoglio, Paolo Maria
Crepaldi, Tiziana
author_sort Gallo, Simona
collection PubMed
description BACKGROUND AND PURPOSE: Doxorubicin anti‐cancer therapy is associated with cardiotoxicity, resulting from DNA damage response (DDR). Hepatocyte growth factor (HGF) protects cardiomyocytes from injury, but its effective use is compromised by low biodistribution. In this study, we have investigated whether the activation of the HGF receptor—encoded by the Met gene—by an agonist monoclonal antibody (mAb) could protect against doxorubicin‐induced cardiotoxicity. EXPERIMENTAL APPROACH: The mAb (5 mg·kg(−1)) was injected in vivo into C57BL/6J mice, before doxorubicin (three doses of 7 mg·kg(−1)). Cardiac functions were evaluated through MRI after treatment termination. Heart histological staining and mRNA levels of genes associated with heart failure (Acta1 and Nppa), inflammation (IL‐6), and fibrosis (Ctgf, Col1a2, Timp1, and Mmp9) were assessed. MAb (100 nM) was administered in vitro to H9c2 cardiomyoblasts before addition of doxorubicin (25 μM). DDR and apoptosis markers were evaluated by quantitative western blotting, flow cytometry, and immunofluorescence. Stattic was used for pharmacological inactivation of STAT3. KEY RESULTS: In vivo, administration of the mAb alleviated doxorubicin‐induced cardiac dysfunction and fibrosis. In vitro, mAb mimicked the response to HGF by (a) inhibiting histone H2AX phosphorylation at S139, (b) quenching the expression of the DNA repair enzyme PARP1, and (c) reducing the proteolytic activation of caspase 3. The MET‐driven cardioprotection involved, at least in vitro, the phosphorylation of STAT3. CONCLUSION AND IMPLICATIONS: The MET agonist mAb provides a new tool for cardioprotection against anthracycline cardiotoxicity.
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spelling pubmed-72800132020-06-10 Activation of the MET receptor attenuates doxorubicin‐induced cardiotoxicity in vivo and in vitro Gallo, Simona Spilinga, Martina Albano, Raffaella Ferrauto, Giuseppe Di Gregorio, Enza Casanova, Elena Balmativola, Davide Bonzano, Alessandro Boccaccio, Carla Sapino, Anna Comoglio, Paolo Maria Crepaldi, Tiziana Br J Pharmacol Research Papers BACKGROUND AND PURPOSE: Doxorubicin anti‐cancer therapy is associated with cardiotoxicity, resulting from DNA damage response (DDR). Hepatocyte growth factor (HGF) protects cardiomyocytes from injury, but its effective use is compromised by low biodistribution. In this study, we have investigated whether the activation of the HGF receptor—encoded by the Met gene—by an agonist monoclonal antibody (mAb) could protect against doxorubicin‐induced cardiotoxicity. EXPERIMENTAL APPROACH: The mAb (5 mg·kg(−1)) was injected in vivo into C57BL/6J mice, before doxorubicin (three doses of 7 mg·kg(−1)). Cardiac functions were evaluated through MRI after treatment termination. Heart histological staining and mRNA levels of genes associated with heart failure (Acta1 and Nppa), inflammation (IL‐6), and fibrosis (Ctgf, Col1a2, Timp1, and Mmp9) were assessed. MAb (100 nM) was administered in vitro to H9c2 cardiomyoblasts before addition of doxorubicin (25 μM). DDR and apoptosis markers were evaluated by quantitative western blotting, flow cytometry, and immunofluorescence. Stattic was used for pharmacological inactivation of STAT3. KEY RESULTS: In vivo, administration of the mAb alleviated doxorubicin‐induced cardiac dysfunction and fibrosis. In vitro, mAb mimicked the response to HGF by (a) inhibiting histone H2AX phosphorylation at S139, (b) quenching the expression of the DNA repair enzyme PARP1, and (c) reducing the proteolytic activation of caspase 3. The MET‐driven cardioprotection involved, at least in vitro, the phosphorylation of STAT3. CONCLUSION AND IMPLICATIONS: The MET agonist mAb provides a new tool for cardioprotection against anthracycline cardiotoxicity. John Wiley and Sons Inc. 2020-05-29 2020-07 /pmc/articles/PMC7280013/ /pubmed/32133617 http://dx.doi.org/10.1111/bph.15039 Text en © 2020 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Papers
Gallo, Simona
Spilinga, Martina
Albano, Raffaella
Ferrauto, Giuseppe
Di Gregorio, Enza
Casanova, Elena
Balmativola, Davide
Bonzano, Alessandro
Boccaccio, Carla
Sapino, Anna
Comoglio, Paolo Maria
Crepaldi, Tiziana
Activation of the MET receptor attenuates doxorubicin‐induced cardiotoxicity in vivo and in vitro
title Activation of the MET receptor attenuates doxorubicin‐induced cardiotoxicity in vivo and in vitro
title_full Activation of the MET receptor attenuates doxorubicin‐induced cardiotoxicity in vivo and in vitro
title_fullStr Activation of the MET receptor attenuates doxorubicin‐induced cardiotoxicity in vivo and in vitro
title_full_unstemmed Activation of the MET receptor attenuates doxorubicin‐induced cardiotoxicity in vivo and in vitro
title_short Activation of the MET receptor attenuates doxorubicin‐induced cardiotoxicity in vivo and in vitro
title_sort activation of the met receptor attenuates doxorubicin‐induced cardiotoxicity in vivo and in vitro
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280013/
https://www.ncbi.nlm.nih.gov/pubmed/32133617
http://dx.doi.org/10.1111/bph.15039
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