A critical role for chloride channel-3 (CIC-3) in smooth muscle cell activation and neointima formation.

Journal Article (Journal Article)

OBJECTIVE: We have shown that the chloride-proton antiporter chloride channel-3 (ClC-3) is required for endosome-dependent signaling by the Nox1 NADPH oxidase in SMCs. In this study, we tested the hypothesis that ClC-3 is necessary for proliferation of smooth muscle cells (SMCs) and contributes to neointimal hyperplasia following vascular injury. METHODS AND RESULTS: Studies were performed in SMCs isolated from the aorta of ClC-3-null and littermate control (wild-type [WT]) mice. Thrombin and tumor necrosis factor-α (TNF-α) each caused activation of both mitogen activated protein kinase extracellular signal-regulated kinases 1 and 2 and the matrix-degrading enzyme matrix metalloproteinase-9 and cell proliferation of WT SMCs. Whereas responses to thrombin were preserved in ClC-3-null SMCs, the responses to TNF-α were markedly impaired. These defects normalized following gene transfer of ClC-3. Carotid injury increased vascular ClC-3 expression, and compared with WT mice, ClC-3-null mice exhibited a reduction in neointimal area of the carotid artery 28 days after injury. CONCLUSIONS: ClC-3 is necessary for the activation of SMCs by TNF-α but not thrombin. Deficiency of ClC-3 markedly reduces neointimal hyperplasia following vascular injury. In view of our previous findings, this observation is consistent with a role for ClC-3 in endosomal Nox1-dependent signaling. These findings identify ClC-3 as a novel target for the prevention of inflammatory and proliferative vascular diseases.

Full Text

Duke Authors

Cited Authors

  • Chu, X; Filali, M; Stanic, B; Takapoo, M; Sheehan, A; Bhalla, R; Lamb, FS; Miller, FJ

Published Date

  • February 2011

Published In

Volume / Issue

  • 31 / 2

Start / End Page

  • 345 - 351

PubMed ID

  • 21071705

Pubmed Central ID

  • PMC3025755

Electronic International Standard Serial Number (EISSN)

  • 1524-4636

Digital Object Identifier (DOI)

  • 10.1161/ATVBAHA.110.217604


  • eng

Conference Location

  • United States