ClC-2 knockdown prevents cerebrovascular remodeling via inhibition of the Wnt/ß-catenin signaling pathway.
Cell Mol Biol Lett
; 23: 29, 2018.
Article
em En
| MEDLINE
| ID: mdl-29988306
ABSTRACT
BACKGROUND:
Mishandling of intracellular chloride (Cl-) concentration ([Cl-]i) in cerebrovascular smooth muscle cells is implicated in several pathological processes, including hyperplasia and remodeling. We investigated the effects of ClC-2-mediated Cl- efflux on the proliferation of human brain vascular smooth muscle cells (HBVSMCs) induced by angiotensin II (AngII).METHODS:
Cell proliferation and motility were determined using the CCK-8, bromodeoxyuridine staining, wound healing and invasion assays. ClC-2, PCNA, Ki67, survivin and cyclin D1 expression, and ß-catenin and GSK-3ß phosphorylation were examined using western blotting. Histological analyses were performed using hematoxylin and eosin staining and α-SMA staining.RESULTS:
Our results showed that AngII-induced HBVSMC proliferation was accompanied by a decrease in [Cl-]i and an increase in ClC-2 expression. Inhibition of ClC-2 by siRNA prevented AngII from inducing the efflux of Cl-. AngII-induced HBVSMC proliferation, migration and invasion were significantly attenuated by ClC-2 downregulation. The inhibitory effects of ClC-2 knockout on HBVSMC proliferation and motility were associated with inactivation of the Wnt/ß-catenin signaling pathway, as evidenced by inhibition of ß-catenin phosphorylation and nuclear translocation, and decrease of GSK-3ß phosphorylation and survivin and cyclin D1 expression. Recombinant Wnt3a treatment markedly reversed the effect of ClC-2 knockdown on HBVSMC viability. An in vivo study revealed that knockdown of ClC-2 with shRNA adenovirus ameliorated basilar artery remodeling by inhibiting Wnt/ß-catenin signaling in AngII-treated mice.CONCLUSION:
This study demonstrates that blocking ClC-2-mediated Cl- efflux inhibits AngII-induced cerebrovascular smooth muscle cell proliferation and migration by inhibiting the Wnt/ß-catenin pathway. Our data indicate that downregulation of ClC-2 may be a viable strategy in the prevention of hyperplasia and remodeling of cerebrovascular smooth muscle cells.Palavras-chave
Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Canais de Cloreto
/
Via de Sinalização Wnt
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article