ERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C gene.
Hum Mol Genet
; 25(11): 2220-2233, 2016 06 01.
Article
en En
| MEDLINE
| ID: mdl-27131347
ABSTRACT
Cardiomyopathy caused by lamin A/C gene mutations (LMNA cardiomyopathy) is characterized by increased myocardial fibrosis, which impairs left ventricular relaxation and predisposes to heart failure, and cardiac conduction abnormalities. While we previously discovered abnormally elevated extracellular signal-regulated kinase 1/2 (ERK1/2) activities in heart in LMNA cardiomyopathy, its role on the development of myocardial fibrosis remains unclear. We now showed that transforming growth factor (TGF)-ß/Smad signaling participates in the activation of ERK1/2 signaling in LMNA cardiomyopathy. ERK1/2 acts on connective tissue growth factor (CTGF/CCN2) expression to mediate the myocardial fibrosis and left ventricular dysfunction. Studies in vivo demonstrate that inhibiting CTGF/CCN2 using a specific antibody decreases myocardial fibrosis and improves the left ventricular dysfunction. Together, these findings show that cardiac ERK1/2 activity is modulated in part by TGF-ß/Smad signaling, leading to altered activation of CTGF/CCN2 to mediate fibrosis and alter cardiac function. This identifies a novel mechanism in the development of LMNA cardiomyopathy.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Fibrosis
/
Factor de Crecimiento Transformador beta
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Lamina Tipo A
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Factor de Crecimiento del Tejido Conjuntivo
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Cardiomiopatías
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Año:
2016
Tipo del documento:
Article