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ClC-2 knockdown prevents cerebrovascular remodeling via inhibition of the Wnt/?-catenin signaling pathway.

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 ?-catenin and GSK-3? phosphorylation were examined using western blotting. Histological analyses were performed using hematoxylin and eosin staining and ?-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/?-catenin signaling pathway, as evidenced by inhibition of ?-catenin phosphorylation and nuclear translocation, and decrease of GSK-3? 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/?-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/?-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.

SUBMITTER: Lu J

PROVIDER: S-EPMC6022329 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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ClC-2 knockdown prevents cerebrovascular remodeling via inhibition of the Wnt/β-catenin signaling pathway.

Lu Jingjing J Xu Feng F Zhang Yingna Y Lu Hong H Zhang Jiewen J

Cellular & molecular biology letters 20180627

<h4>Background</h4>Mishandling of intracellular chloride (Cl<sup>-</sup>) concentration ([Cl<sup>-</sup>]<sub>i</sub>) in cerebrovascular smooth muscle cells is implicated in several pathological processes, including hyperplasia and remodeling. We investigated the effects of ClC-2-mediated Cl<sup>-</sup> efflux on the proliferation of human brain vascular smooth muscle cells (HBVSMCs) induced by angiotensin II (AngII).<h4>Methods</h4>Cell proliferation and motility were determined using the CCK- ...[more]

PMID: 29988306

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Project description:BackgroundThe serum levels of sclerostin (SOST) are significant elevated in patients with pathological cardiac remodeling after myocardial infarction (MI). However, the mechanisms of SOST in cardiac remodeling remain largely uncharacterized.MethodsCollecting patients with MI who presented with or without left ventricular (LV) remodeling, we investigated differences in SOST expression. The influence of overexpression and silenced of SOST on the angiogenesis of cardiac microvascular endothelial cells (CMECs) was explored through in vitro experiments, and the impact of SOST on Wnt signaling marker proteins was examined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot. Finally, we observed the effects of SOST on cardiac function and morphology in mice MI model, and verified the role of the Wnt signaling marker proteins in vivo.ResultsSerum SOST was significantly increased in patients with cardiac remodeling. Increased SOST expression was also observed in the infarcted hearts of C57BL/6 mice that underwent ligation of the left anterior descending branch of the coronary artery to induce MI. Furthermore, loss and gain of function experiments were conducted to investigate the role of SOST in post-infarct cardiac remodeling in vivo and in vitro. Overexpression of SOST promoted the proliferation and migration of cardiac fibroblasts (CFs), and inhibited angiogenesis of CMECs. In addition, overexpressing SOST in mice significantly deteriorated the post-infarct cardiac remodeling, as shown by the increased LV end systolic and end diastolic dimensions, decreased ejection fraction, and increased myocyte cross-section area and myocardial fibrosis. However, suppressing SOST expression showed the opposite results. The expression of Wnt signaling marker proteins was inhibited after overexpression of SOST, and enhanced after suppression of SOST in vivo and in vitro, suggesting involvement of the Wnt signaling pathway.ConclusionsThe present study demonstrated that SOST aggravates post-infarct pathological myocardial remodeling by inhibiting angiogenesis of CMECs while promoting the proliferation of CFs, and this may be mediated by the Wnt signaling pathway. These results suggested that SOST might act as a biomarker to predict detrimental postinfarct cardiac remodeling, and may be a potential therapeutic target for the treatment of MI.

Dataset Information

ClC-2 knockdown prevents cerebrovascular remodeling via inhibition of the Wnt/?-catenin signaling pathway.

Publications

ClC-2 knockdown prevents cerebrovascular remodeling via inhibition of the Wnt/β-catenin signaling pathway.

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