Protease-activated receptor 1 activation enhances doxorubicin-induced cardiotoxicity.
J Mol Cell Cardiol
; 122: 80-87, 2018 09.
Article
em En
| MEDLINE
| ID: mdl-30098988
ABSTRACT
OBJECTIVE:
The anti-cancer anthracycline drug Doxorubicin (Dox) causes cardiotoxicity. We investigated the role of protease-activated receptor 1 (PAR-1) in Dox-induced cardiotoxicity. METHODS ANDRESULTS:
In vitro experiments revealed that PAR-1 enhanced Dox-induced mitochondrial dysfunction, reactive oxygen species and cell death of cardiac myocytes and cardiac fibroblasts. The contribution of PAR-1 to Dox-induced cardiotoxicity was investigated by subjecting PAR-1-/- mice and PAR-1+/+ mice to acute and chronic exposure to Dox. Heart function was measured by echocardiography. PAR-1-/- mice exhibited significant less cardiac injury and dysfunction compared to PAR-1+/+ mice after acute and chronic Dox administration. PAR-1-/- mice had reduced levels of nitrotyrosine, apoptosis and inflammation in their heart compared to PAR-1+/+ mice. Furthermore, inhibition of PAR-1 in wild-type mice with vorapaxar significantly reduced the acute Dox-induced cardiotoxicity.CONCLUSION:
Our results indicate that activation of PAR-1 contributes to Dox-induced cardiotoxicity. Inhibition of PAR-1 may be a new approach to reduce Dox-induced cardiotoxicity in cancer patients.Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Doxorrubicina
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Receptor PAR-1
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Cardiotoxicidade
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Antibióticos Antineoplásicos
Limite:
Animals
Idioma:
En
Revista:
J Mol Cell Cardiol
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Nova Caledônia