Caveolin-1 expression by means of p38β mitogen-activated protein kinase mediates the antiproliferative effect of carbon monoxide
Caveolin-1 expression by means of p38β mitogen-activated protein kinase mediates the antiproliferative effect of carbon monoxide
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DOI：
10.1073/pnas.0501345102
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发表时间：
2005-08-09
影响因子：
11.1
通讯作者：
Choi, AMK
中科院分区：
文献类型：
--
作者：
Kim, HP;Wang, X;Choi, AMK
在血管损伤过程中，平滑肌细胞的增殖和迁移会导致特征性的新内膜形成，这种情况会因 Caveolin-1 或血红素加氧酶 1 (HO-1) 的基因缺失而加剧，并受到一氧化碳 (CO)（血红素加氧酶 1 活性的副产物）的抑制。 CO通过激活p38丝裂原激活蛋白激酶(MAPK)和p21(Waf1/Cip1)抑制平滑肌细胞增殖。暴露于 CO 会通过激活鸟苷酸环化酶和 p38 MAPIK 增加受损主动脉新生内膜病变中的 Caveolin-1 表达。 p38 beta(-/-) 成纤维细胞不会响应 CO 诱导 Caveolin-1，并且表现出基础 Caveolin-1 表达减少，但通过 p38 beta 基因转移得以恢复。 p38 beta MAPK 下调细胞外信号调节蛋白激酶 1/2 (ERK-1/2)，从而抑制 Caveolin-1 转录。 Caveolin-1 的基因缺失消除了 CO 的抗增殖作用。因此，我们证明 CO 通过激活 p38 beta MAPK 上调 Caveolin-1，而 Caveolin-1 充当肿瘤抑制蛋白，介导这种气体的生长抑制特性。
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 p21(Waf1/Cip1). Exposure to CO increased caveolin-1 expression in neointimal lesions of injured aorta and in vitro by activating guanylyl cyclase and p38 MAPIK. p38 beta(-/-) fibroblasts did not induce caveolin-1 in response to CO, and exhibited a diminished basal caveolin-1 expression, which was restored by p38 beta gene transfer. p38 beta MAPK 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 beta MAPK, up-regulates caveolin-1, which acts as a tumor suppressor protein that mediates the growth inhibitory properties of this gas.