Cthrc1 is a novel inhibitor of transforming growth factor-β signaling and neointimal lesion formation
Cthrc1 is a novel inhibitor of transforming growth factor-β signaling and neointimal lesion formation
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DOI：
10.1161/01.res.0000260806.99307.72
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发表时间：
2007-03-30
影响因子：
20.1
通讯作者：
Lindner, Volkhard
中科院分区：
文献类型：
--
作者：
LeClair, Renee J.;Durmus, Tahir;Lindner, Volkhard
我们将含有 1 (Cthrc1) 的胶原三螺旋重复序列确定为在动脉损伤的外膜和新内膜中表达的新基因，并发现它在功能上增加细胞迁移，同时减少胶原沉积。为了解决 Cthrc1 的体内作用，我们生成了组成型过表达 Cthrc1 的转基因小鼠品系。两个转基因品系的杂交产生的后代由于胶原骨基质减少而骨骼脆弱。半合子 Cthrc1 转基因小鼠发育正常，但与野生型同窝小鼠相比，颈动脉结扎引起的新内膜病变形成和外膜胶原沉积显着减少。在 75% 的 Cthrc1 转基因小鼠中，通过阿尔新蓝染色和软骨细胞标记物 II 型胶原蛋白的表达进行评估，观察到内侧平滑肌细胞的软骨化生。 Cthrc1 转基因动脉平滑肌细胞中转化生长因子-β 信号传导减少，磷酸化 Smad2/3 免疫反应性降低证明了这一点，而与骨形态发生蛋白相关的 Smad 信号传导不受影响。同样，原代平滑肌细胞和过度表达 Cthrc1 的 PAC1 平滑肌细胞的磷酸化 Smad2/3 和前胶原水平降低。此外，Cthrc1 抑制平滑肌中的转化生长因子-β 敏感报告基因构建体，但不抑制内皮细胞。这些数据表明，Cthrc1 是转化生长因子-β 的细胞类型特异性抑制剂，进而影响 I 型和 III 型胶原沉积、新内膜形成和平滑肌细胞去分化。
We identified collagen triple helix repeat containing-1 ( Cthrc1) as a novel gene expressed in the adventitia and neointima on arterial injury and found that it functionally increases cell migration while reducing collagen deposition. To address the in vivo role of Cthrc1, we generated transgenic mouse lines that constitutively overexpress Cthrc1. An intercross of 2 transgenic lines produced offspring with brittle bones caused by a reduction in collagenous bone matrix. Hemizygous Cthrc1 transgenic mice developed normally but neointimal lesion formation and adventitial collagen deposition in response to carotid artery ligation were significantly reduced compared with wild-type littermates. In 75% of Cthrc1 transgenic mice, cartilaginous metaplasia of medial smooth muscle cells was observed as assessed by Alcian blue staining and expression of the chondrocyte marker collagen type II. Transforming growth factor-beta signaling was reduced in smooth muscle cells of Cthrc1 transgenic arteries, as demonstrated by reduced phospho-Smad2/3 immunoreactivity, whereas Smad signaling related to bone morphogenetic proteins was unaffected. Similarly, primary smooth muscle cells and PAC1 smooth muscle cells overexpressing Cthrc1 had reduced levels of phospho-Smad2/3 as well as procollagen. Furthermore, Cthrc1 inhibited transforming growth factor-beta-sensitive reporter constructs in smooth muscle but not endothelial cells. These data indicate that Cthrc1 is a cell-type-specific inhibitor of transforming growth factor-beta, which in turn impacts collagen type I and III deposition, neointimal formation, and dedifferentiation of smooth muscle cells.