TGF-ß1 affects cell-cell adhesion in the heart in an NCAM1-dependent mechanism.
J Mol Cell Cardiol
; 112: 49-57, 2017 11.
Article
en En
| MEDLINE
| ID: mdl-28870505
ABSTRACT
The contractile property of the myocardium is maintained by cell-cell junctions enabling cardiomyocytes to work as a syncytium. Alterations in cell-cell junctions are observed in heart failure, a disease characterized by the activation of Transforming Growth Factor beta 1 (TGFß1). While TGFß1 has been implicated in diverse biologic responses, its molecular function in controlling cell-cell adhesion in the heart has never been investigated. Cardiac-specific transgenic mice expressing active TGFß1 were generated to model the observed increase in activity in the failing heart. Activation of TGFß1 in the heart was sufficient to drive ventricular dysfunction. To begin to understand the function of this important molecule we undertook an extensive structural analysis of the myocardium by electron microscopy and immunostaining. This approach revealed that TGFß1 alters intercalated disc structures and cell-cell adhesion in ventricular myocytes. Mechanistically, we found that TGFß1 induces the expression of neural adhesion molecule 1 (NCAM1) in cardiomyocytes in a p38-dependent pathway, and that selective targeting of NCAM1 was sufficient to rescue the cell adhesion defect observed when cardiomyocytes were treated with TGFß1. Importantly, NCAM1 was upregulated in human heart samples from ischemic and non-ischemic cardiomyopathy patients and NCAM1 protein levels correlated with the degree of TGFß1 activity in the human cardiac ventricle. Overall, we found that TGFß1 is deleterious to the heart by regulating the adhesion properties of cardiomyocytes in an NCAM1-dependent mechanism. Our results suggest that inhibiting NCAM1 would be cardioprotective, counteract the pathological action of TGFß1 and reduce heart failure severity.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Antígeno CD56
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Factor de Crecimiento Transformador beta1
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Miocardio
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
J Mol Cell Cardiol
Año:
2017
Tipo del documento:
Article