| First Author | Chu X | Year | 2011 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 31 |
| Issue | 2 | Pages | 345-51 |
| PubMed ID | 21071705 | Mgi Jnum | J:184184 |
| Mgi Id | MGI:5320396 | Doi | 10.1161/ATVBAHA.110.217604 |
| Citation | Chu X, et al. (2011) A critical role for chloride channel-3 (CIC-3) in smooth muscle cell activation and neointima formation. Arterioscler Thromb Vasc Biol 31(2):345-51 |
| abstractText | 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-alpha (TNF-alpha) 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-alpha 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-alpha 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. |
