Defective pulmonary vascular remodeling in Smad8 mutant mice
Defective pulmonary vascular remodeling in Smad8 mutant mice
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DOI：
10.1093/hmg/ddp214
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发表时间：
2009-08-01
影响因子：
3.5
通讯作者：
Martin, James F.
中科院分区：
文献类型：
--
作者：
Huang, Zheng;Wang, Degang;Martin, James F.
肺动脉高压（PAH）是一种导致肺动脉树病理变化的进行性致死性疾病，最终导致右心衰竭。在PAH家族中鉴定II型骨形态发生蛋白（Bmp）受体BmpRII突变的工作涉及PAH发病机制中的Bmp信号传导。然而，PAH中BmpRII下游的效应子仍不清楚，因为BmpRII通过Smad依赖性和独立性机制进行信号传导。我们研究了Smad 8功能，一个趋异受体调节Smad的Bmp信号下游，在小鼠中使用基因靶向。我们发现，成年人Smad 8功能丧失导致远端肺动脉的特征性变化，包括在PAH患者中观察到的中膜增厚和平滑肌增生。Smad 8突变型肺血管系统具有激活素/TGF β信号转导上调和病理性重塑，伴有异常Prx 1和Tenascin-C表达。Smad 8突变体的一个子集有肺腺瘤，揭示了Smad 8在正常生长控制中的功能。这些发现暗示Smad 8在肺动脉高压和肺肿瘤发生中，并支持Smad 8作为人类PAH的候选基因。
Pulmonary artery hypertension (PAH), a progressive, lethal condition that results in pathologic changes in the pulmonary arterial tree, eventually leads to right heart failure. Work identifying mutations in the Type II Bone morphogenetic protein (Bmp) receptor, BmpRII, in families with PAH has implicated Bmp-signaling in the pathogenesis of PAH. However, the effectors downstream of BmpRII in PAH remain unclear since BmpRII signals via Smad-dependent and independent mechanisms. We investigated Smad8 function, a divergent receptor regulated Smad downstream of Bmp-signaling, using gene targeting in mice. We show that Smad8 loss of function in adults resulted in characteristic changes in distal pulmonary arteries including medial thickening and smooth muscle hyperplasia that is observed in patients with PAH. Smad8 mutant pulmonary vasculature had upregulated Activin/Tgf beta signaling and pathologic remodeling with aberrant Prx1 and Tenascin-C expression. A subset of Smad8 mutants had pulmonary adenomas uncovering a function for Smad8 in normal growth control. These findings implicate Smad8 in both pulmonary hypertension and lung tumorigenesis and support Smad8 as a candidate gene for PAH in humans.