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

Chu X, Filali M, Stanic B, Takapoo M, Sheehan A, Bhalla R, Lamb FS, Miller FJ
Arterioscler Thromb Vasc Biol. 2011 31 (2): 345-51

PMID: 21071705 · PMCID: PMC3025755 · DOI:10.1161/ATVBAHA.110.217604

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.

MeSH Terms (18)

Animals Cell Proliferation Cells, Cultured Chloride Channels Endosomes Hyperplasia Matrix Metalloproteinase 9 Mice Mice, Knockout Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Models, Animal Muscle, Smooth, Vascular NADH, NADPH Oxidoreductases NADPH Oxidase 1 Neointima Signal Transduction Tumor Necrosis Factor-alpha

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