Exogenous ubiquitin modulates chronic ß-adrenergic receptor-stimulated myocardial remodeling: role in Akt activity and matrix metalloproteinase expression.
Am J Physiol Heart Circ Physiol
; 303(12): H1459-68, 2012 Dec 15.
Article
em En
| MEDLINE
| ID: mdl-23042947
ABSTRACT
ß-Adrenergic receptor (ß-AR) stimulation increases extracellular ubiquitin (UB) levels, and extracellular UB inhibits ß-AR-stimulated apoptosis in adult cardiac myocytes. This study investigates the role of exogenous UB in chronic ß-AR-stimulated myocardial remodeling. l-Isoproterenol (ISO; 400 µg·kg(-1)·h(-1)) was infused in mice in the presence or absence of UB (1 µg·g(-1)·h(-1)). Left ventricular (LV) structural and functional remodeling was studied 7 days after infusion. UB infusion enhanced serum UB levels. In most parts, UB alone had no effect on morphometric or functional parameters. Heart weight-to-body weight ratios were increased to a similar extent in the ISO and UB + ISO groups. Echocardiographic analyses showed increased percent fractional shortening, ejection fraction, and LV circumferential stress and fiber-shortening velocity in the ISO group. These parameters were significantly lower in UB + ISO vs. ISO. Isovolumic contraction and relaxation times and ejection time were significantly lower in ISO vs. UB + ISO. The increase in the number of TUNEL-positive myocytes and fibrosis was significantly higher in ISO vs. UB + ISO. Activation of Akt was higher, whereas activation of GSK-3ß and JNKs was lower in UB + ISO vs ISO. Expression of MMP-2, MMP-9, and TIMP-2 was higher in UB + ISO vs ISO. In isolated cardiac fibroblasts, UB enhanced expression of MMP-2 and TIMP-2 in the presence of ISO. Neutralizing UB antibodies negated the effects of UB on MMP-2 expression, whereas recombinant UB enhanced MMP-2 expression. UB activated Akt, and inhibition of Akt inhibited UB + ISO-mediated increases in MMP-2 expression. Thus, exogenous UB plays an important role in ß-AR-stimulated myocardial remodeling with effects on LV function, fibrosis, and myocyte apoptosis.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Receptores Adrenérgicos beta
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Remodelação Ventricular
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Metaloproteinase 2 da Matriz
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Metaloproteinase 9 da Matriz
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Ubiquitina
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Proteínas Proto-Oncogênicas c-akt
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article