Contribution of MLKL to the development of doxorubicin-induced cardiomyopathy and its amelioration by rapamycin.
J Pharmacol Sci
; 156(1): 9-18, 2024 Sep.
Article
en En
| MEDLINE
| ID: mdl-39068035
ABSTRACT
Necroptosis, necrosis characterized by RIPK3-MLKL activation, has been proposed as a mechanism of doxorubicin (DOX)-induced cardiomyopathy. We showed that rapamycin, an mTORC1 inhibitor, attenuates cardiomyocyte necroptosis. Here we examined role of MLKL in DOX-induced myocardial damage and protective effects of rapamycin. Cardiomyopathy was induced in mice by intraperitoneal injections of DOX (10 mg/kg, every other day) and followed for 7 days. DOX-treated mice showed a significant decline in LVEF assessed by cardiac MRI (45.5 ± 5.1% vs. 65.4 ± 4.2%), reduction in overall survival rates, and increases in myocardial RIPK3 and MLKL expression compared with those in vehicle-treated mice, and those changes were prevented by administration of rapamycin (0.25 mg/kg) before DOX injection. In immunohistochemical analyses, p-MLKL signals were detected in the cardiomyocytes of DOX-treated mice, and the signals were reduced by rapamycin. Mlkl+/- and Mlkl-/- mice were similarly resistant to DOX-induced cardiac dysfunction, indicating that a modest reduction in MLKL level is sufficient to prevent the development of DOX-induced cardiomyopathy. However, evidence of cardiomyocyte necrosis assessed by C9 immunostaining, presence of replacement fibrosis, and electron microscopic analyses was negligible in the myocardium of DOX-treated mice. Thus, MLKL-mediated signaling contributes to DOX-induced cardiac dysfunction primarily by a necrosis-independent mechanism, which is inhibitable by rapamycin.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Quinasas
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Doxorrubicina
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Sirolimus
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Miocitos Cardíacos
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Proteína Serina-Treonina Quinasas de Interacción con Receptores
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Necroptosis
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Ratones Endogámicos C57BL
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Cardiomiopatías
Límite:
Animals
Idioma:
En
Revista:
J Pharmacol Sci
Asunto de la revista:
FARMACOLOGIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Japón