Puma deletion delays cardiac dysfunction in murine heart failure models through attenuation of apoptosis.
Circulation
; 124(1): 31-9, 2011 Jul 05.
Article
en En
| MEDLINE
| ID: mdl-21670227
ABSTRACT
BACKGROUND:
Puma (p53-upregulated modulator of apoptosis) is a proapoptotic Bcl-2 family protein that serves as a general sensor in response to pathological apoptotic stimuli. In previous work, we demonstrated that puma ablation protects the heart from reperfusion injury in a Langendorff setting. Consistent with this, downregulation of Puma in isolated cardiac myocytes prevented apoptosis induced by different proapoptotic agents. Here, we extended our research to investigate the role of Puma, a downstream mediator of p53, in the development of heart failure using Puma(-/-) mice. METHODS ANDRESULTS:
Mice underwent transverse aortic constriction, and the characteristics of cardiac remodeling were analyzed by echocardiography, histology, and gene expression at multiple time points after surgery. Four weeks after the operation, puma deletion attenuated pressure overload-induced apoptosis and fibrosis; however, it did not affect hypertrophy and angiogenesis and maintained functional performance (fractional shortening, 39% versus 25.2% in Puma(-/-) versus WT mice, respectively). Even at 12 weeks after transverse aortic constriction, Puma(-/-) mice displayed only slightly reduced contractility. In addition, transverse aortic constriction induced puma expression in a partially p53-dependent manner. To corroborate these findings, we studied another heart failure model in which heart-specific mdm4 deletion leads to p53 activation and dilated cardiomyopathy. In these mice, Puma was upregulated and its deletion rescued the cardiomyopathy phenotype.CONCLUSIONS:
Our data indicate that Puma might be a critical component of the apoptotic signaling pathways that contribute to ventricular remodeling and heart failure. Therefore, Puma inactivation may serve as a preferential target to prevent heart failure induced by cellular stress.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Apoptosis
/
Progresión de la Enfermedad
/
Proteínas Supresoras de Tumor
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Proteínas Reguladoras de la Apoptosis
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Corazón
/
Insuficiencia Cardíaca
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Circulation
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos