During vascular injury, the proliferation and migration of smooth muscle cells leads to characteristic neointima formation, which can be exacerbated by genetic depletion of caveolin-1 or heme oxygenase 1 (HO-1), and inhibited by carbon monoxide (CO), a by-product of heme oxygenase 1 activity. CO inhibited smooth muscle cell proliferation by activating p38 mitogen-activated protein kinase (MAPK) and p21Waf1/ciP1. Exposure to CO increased caveolin-1 expression in neointimal lesions of injured aorta and in vitro by activating guanylyl cyclase and p38 MAPK. p38β-/- fibroblasts did not induce caveolin-1 in response to CO, and exhibited a diminished basal caveolin-1 expression, which was restored by p38/B gene transfer. p38/3 WIAPK down-regulated extracellular signal-regulated protein kinase 1/2 (ERK-1/2), which can repress caveolin-1 transcription. Genetic depletion of caveolin-1 abolished the antiproliferative effect of CO. Thus, we demonstrate that CO, by activating p38/3 MAPK, up-regulates caveolin-1, which acts as a tumor suppressor protein that mediates the growth inhibitory properties of this gas.
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - Aug 9 2005|
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