Tojais Nancy F, Cao Aiqin, Lai Ying-Ju, Wang Lingli, Chen Pin-I, Alcazar Miguel A Alejandre, de Jesus Perez Vinicio A, Hopper Rachel K, Rhodes Christopher J, Bill Matthew A, Sakai Lynn Y, Rabinovitch Marlene
From the Department of Pediatrics (N.F.T., A.C., Y.-J.L., L.W., P.I.C., M.A.A.A., R.K.H., C.J.R., M.R.) and Department of Medicine (V.A.d.J.P., M.A.B.), the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA; and Shriners Hospital for Children, Oregon Health & Science University, Portland (L.Y.S.).
Arterioscler Thromb Vasc Biol. 2017 Aug;37(8):1559-1569. doi: 10.1161/ATVBAHA.117.309696. Epub 2017 Jun 15.
We determined in patients with pulmonary arterial (PA) hypertension (PAH) whether in addition to increased production of elastase by PA smooth muscle cells previously reported, PA elastic fibers are susceptible to degradation because of their abnormal assembly.
Fibrillin-1 and elastin are the major components of elastic fibers, and fibrillin-1 binds bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-β1 (TGFβ1). Thus, we considered whether BMPs like TGFβ1 contribute to elastic fiber assembly and whether this process is perturbed in PAH particularly when the BMP receptor, BMPR2, is mutant. We also assessed whether in mice with compound heterozygosity, elastic fibers are susceptible to degradation. In PA smooth muscle cells and adventitial fibroblasts, TGFβ1 increased elastin mRNA, but the elevation in elastin protein was dependent on BMPR2; TGFβ1 and BMP4, via BMPR2, increased extracellular accumulation of fibrillin-1. Both BMP4- and TGFβ1-stimulated elastic fiber assembly was impaired in idiopathic (I) PAH-PA adventitial fibroblast versus control cells, particularly those with hereditary (H) PAH and a mutation. This was related to profound reductions in elastin and fibrillin-1 mRNA. Elastin protein was increased in IPAH PA adventitial fibroblast by TGFβ1 but only minimally so in mutant cells. Fibrillin-1 protein increased only modestly in IPAH or HPAH PA adventitial fibroblasts stimulated with BMP4 or TGFβ1. In heterozygote mice, reduced PA fibrillin-1 was associated with elastic fiber susceptibility to degradation and more severe pulmonary hypertension.
Disrupting BMPR2 impairs TGFβ1- and BMP4-mediated elastic fiber assembly and is of pathophysiologic significance in PAH.
我们在肺动脉（PA）高压（PAH）患者中确定，除了先前报道的PA平滑肌细胞弹性蛋白酶产生增加外，PA弹性纤维是否因其异常组装而易于降解。
原纤维蛋白-1和弹性蛋白是弹性纤维的主要成分，原纤维蛋白-1结合骨形态发生蛋白（BMPs）和转化生长因子-β1（TGFβ1）的大潜伏复合物。因此，我们考虑BMPs如TGFβ1是否有助于弹性纤维组装，以及该过程在PAH中是否受到干扰，特别是当BMP受体BMPR2发生突变时。我们还评估了在复合杂合子小鼠中，弹性纤维是否易于降解。在PA平滑肌细胞和外膜成纤维细胞中，TGFβ1增加了弹性蛋白mRNA，但弹性蛋白蛋白的升高依赖于BMPR2；TGFβ1和BMP4通过BMPR2增加了原纤维蛋白-1的细胞外积累。与对照细胞相比，特发性（I）PAH-PA外膜成纤维细胞中，BMP4和TGFβ1刺激的弹性纤维组装均受损，尤其是那些具有遗传性（H）PAH和突变的细胞。这与弹性蛋白和原纤维蛋白-1 mRNA的显著降低有关。TGFβ1使IPAH PA外膜成纤维细胞中的弹性蛋白蛋白增加，但在突变细胞中仅略有增加。在用BMP4或TGFβ1刺激的IPAH或HPAH PA外膜成纤维细胞中，原纤维蛋白-1蛋白仅适度增加。在杂合子小鼠中，PA原纤维蛋白-1减少与弹性纤维易于降解和更严重的肺动脉高压有关。
破坏BMPR2会损害TGFβ1和BMP4介导的弹性纤维组装，并且在PAH中具有病理生理学意义。
