Notch1 inhibition reduces low shear stress-induced plaque formation.
Int J Biochem Cell Biol
; 72: 63-72, 2016 Mar.
Article
en En
| MEDLINE
| ID: mdl-26783939
Low shear stress (LSS) contributes to the pathogenesis of inflammatory diseases, such as atherosclerosis. Notch1 is a type I transmembrane receptor that critically determines the growth, differentiation, and survival of various cell types, but its role and mechanism in LSS-induced inflammatory response remains undetermined. Apolipoprotein E-deficient (ApoE(-/-)) mice were fed with high fat diet and administered intraperitoneally with DAPT (a γ-secretase inhibitor). Perivascular shear stress modifiers were placed around the right carotid arteries to induce LSS. The left carotid arteries with undisturbed shear stress (USS) were used as the control. LSS increased Delta-like 1 (DLL-1) protein expression and the expression of Notch1 and NICD, while DAPT administration reduced NICD expression. Compared with the LSS group, DAPT reduced LSS-induced plaque formation and intercellular adhesion molecule 1 (ICAM-1) expression. Human umbilical vein endothelial cells (HUVECs) were exposure to undisturbed shear stress (USS, 1Pa) or LSS (0.4Pa). Notch1 was inhibited by siRNA or DAPT. RT-PCR and western blotting analysis showed that LSS upregulated the expression of Notch1 in a time-dependent manner. Caveolin-1 (CAV1) inhibition by siRNA could reduce Notch1 and NICD expression. Compared with USS, LSS increased inflammatory response, including IL-1ß and IL-6 secretion, ICAM-1 and inducible nitric oxide synthase (iNOS) expression, and THP-1 cells adhesion. Notch1 inhibition by siRNA or DAPT could reduce these inflammatory responses by reduction of NF-κB phosphorylation, upregulation of IkBα expression, and inhibition of nuclear translocation of NF-κB, while Notch1 activation by DLL-4 had an adverse effect. The Notch signaling system is therefore a potential target for modulating LSS-induced inflammation response during atherosclerosis.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Estrés Mecánico
/
Resistencia al Corte
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Receptor Notch1
/
Placa Aterosclerótica
Idioma:
En
Revista:
Int J Biochem Cell Biol
Asunto de la revista:
BIOQUIMICA
Año:
2016
Tipo del documento:
Article
Pais de publicación:
Países Bajos