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

British Journal of Pharmacology
Simona GalloTiziana Crepaldi

Abstract

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. 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. In vivo, administration of the mAb alleviated doxorubicin-induced cardiac dysfunction and fibrosis. In vitro, mAb mimicked the response to HGF by (a) inhibiting his...Continue Reading

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Citations

Jun 15, 2020·British Journal of Pharmacology·Ion CristóbalJesús García-Foncillas
Apr 9, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Mengjie XiaoJunlian Gu

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Methods Mentioned

BETA
PCR
Assay
Protein Assay
electrophoresis
flow cytometry
fluorescence microscopy
nuclear translocation

Key Resources (RRID) Mentioned

IMSR_JAX
SCR_003070
AB_2118009
AB_397274
AB_2795959
SCR_002798
CVCL_0286

Software Mentioned

LAS AF Leica
ImageJ
LAS AF
Image Lab
GraphPad Prism
ARRIVE

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