ClC-2 knockdown prevents cerebrovascular remodeling via inhibition of the Wnt/βcatenin signaling pathway

• Autorzy: Lu J. , Xu F. , Zhang G. , Lu H. , Zhang J.
• Języki publikacji: EN

Abstrakty

EN

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 β-catenin and GSK-3β 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/β-catenin signaling pathway, as evidenced by inhibition of β-catenin phosphorylation and nuclear translocation, and decrease of GSK-3β 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/β-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/β-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.

• Wydawca: -
• Czasopismo: Cellular and Molecular Biology Letters
• Rocznik: 2018
• Tom: 23
• Opis fizyczny: p.1-13,fig.,ref.

Twórcy

autor

Lu J.

• Department of Neurology, Henan People’s Hospital, No. 7 Wai-5 Road, Zhengzhou 450052, Henan Province, China

autor

Xu F.

• Department of Neurology, Henan People’s Hospital, No. 7 Wai-5 Road, Zhengzhou 450052, Henan Province, China

autor

Zhang G.

• Department of Neurology, Henan People’s Hospital, No. 7 Wai-5 Road, Zhengzhou 450052, Henan Province, China

autor

Lu H.

• Department of Neurology, Henan People’s Hospital, No. 7 Wai-5 Road, Zhengzhou 450052, Henan Province, China

autor

Zhang J.

• Department of Neurology, Henan People’s Hospital, No. 7 Wai-5 Road, Zhengzhou 450052, Henan Province, China

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Identyfikatory

DOI

10.1186/s11658-018-0095-z