Sustained hemodynamic stress disrupts normal circadian rhythms in calcineurin-dependent signaling and protein phosphorylation in the heart.
Circ Res
; 108(4): 437-45, 2011 Feb 18.
Article
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| MEDLINE
| ID: mdl-21233454
ABSTRACT
RATIONALE Despite overwhelming evidence of the importance of circadian rhythms in cardiovascular health and disease, little is known regarding the circadian regulation of intracellular signaling pathways controlling cardiac function and remodeling. OBJECTIVE:
To assess circadian changes in processes dependent on the protein phosphatase calcineurin, relative to changes in phosphorylation of cardiac proteins, in normal, hypertrophic, and failing hearts. METHODS ANDRESULTS:
We found evidence of large circadian oscillations in calcineurin-dependent activities in the left ventricle of healthy C57BL/6 mice. Calcineurin-dependent transcript levels and nuclear occupancy of the NFAT (nuclear factor of activated T cells) regularly fluctuated as much as 20-fold over the course of a day, peaking in the morning when mice enter a period of rest. Phosphorylation of the protein phosphatase 1 inhibitor 1 (I-1), a direct calcineurin substrate, and phospholamban, an indirect target, oscillated directly out of phase with calcineurin-dependent signaling. Using a surgical model of cardiac pressure overload, we found that although calcineurin-dependent activities were markedly elevated, the circadian pattern of activation was maintained, whereas, oscillations in phospholamban and I-1 phosphorylation were lost. Changes in the expression of fetal gene markers of heart failure did not mirror the rhythm in calcineurin/NFAT activation, suggesting that these may not be direct transcriptional target genes. Cardiac function in mice subjected to pressure overload was significantly lower in the morning than in the evening when assessed by echocardiography.CONCLUSIONS:
Normal, opposing circadian oscillations in calcineurin-dependent activities and phosphorylation of proteins that regulate contractility are disrupted in heart failure.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Estrés Fisiológico
/
Transducción de Señal
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Proteínas
/
Ritmo Circadiano
/
Calcineurina
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Insuficiencia Cardíaca
/
Hemodinámica
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Circ Res
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos