Abstract：
Pulmonary hypertension (PH) is a progressive, severe and to date not curable disease of the pulmonary vasculature. Alterations of the insulin-like growth factor 1 (IGF-1) system are known to play a role in vascular pathologies and IGF-binding proteins (IGFBPs) are important regulators of the bioavailability and function of IGFs. In this study, we show that circulating plasma levels of IGFBP-1, IGFBP-2 and IGFBP-3 are increased in idiopathic pulmonary arterial hypertension (IPAH) patients compared to healthy individuals. These binding proteins inhibit the IGF-1 induced IGF-1 receptor (IGF1R) phosphorylation and exhibit diverging effects on the IGF-1 induced signaling pathways in human pulmonary arterial cells (i.e. healthy as well as IPAH-hPASMCs, and healthy hPAECs). Furthermore, IGFBPs are differentially expressed in an experimental mouse model of PH. In hypoxic mouse lungs, IGFBP-1 mRNA expression is decreased whereas the mRNA for IGFBP-2 is increased. In contrast to IGFBP-1, IGFBP-2 shows vaso-constrictive properties in the murine pulmonary vasculature. Our analyses show that IGFBP-1 and IGFBP-2 exhibit diverging effects on IGF-1 signaling and display a unique IGF1R-independent kinase activation pattern in human pulmonary arterial smooth muscle cells (hPASMCs), which represent a major contributor of PAH pathobiology. Furthermore, we could show that IGFBP-2, in contrast to IGFBP-1, induces epidermal growth factor receptor (EGFR) signaling, Stat-3 activation and expression of Stat-3 target genes. Based on our results, we conclude that the IGFBP family, especially IGFBP-1, IGFBP-2 and IGFBP-3, are deregulated in PAH, that they affect IGF signaling and thereby regulate the cellular phenotype in PH.
摘要：
肺动脉高压(PH)是一种进行性,严重且迄今为止无法治愈的肺血管疾病。已知胰岛素样生长因子1（IGF-1）系统的改变在血管病变中起作用，并且IGF结合蛋白（IGFBP）是IGF生物利用度和功能的重要调节剂。在这项研究中,我们显示,与健康个体相比,特发性肺动脉高压(IPAH)患者的循环血浆IGFBP-1,IGFBP-2和IGFBP-3水平升高.这些结合蛋白抑制IGF-1诱导的IGF-1受体（IGF1R）磷酸化，并对IGF-1诱导的人肺动脉细胞（即健康以及IPAH-hPASMCs，和健康的hPAECs)。此外，IGFBP在PH的实验小鼠模型中差异表达。在缺氧的小鼠肺部，IGFBP-1mRNA表达减少,而IGFBP-2的mRNA增加。与IGFBP-1相反,IGFBP-2在鼠肺脉管系统中显示血管收缩特性。我们的分析表明，IGFBP-1和IGFBP-2对IGF-1信号传导表现出不同的作用，并在人肺动脉平滑肌细胞（hPASMC）中显示出独特的IGF1R非依赖性激酶激活模式。这代表了PAH病理生物学的主要贡献者。此外，我们可以证明IGFBP-2与IGFBP-1相反，可以诱导表皮生长因子受体（EGFR）信号，Stat-3活化和Stat-3靶基因的表达。根据我们的结果,我们得出结论，IGFBP家族，特别是IGFBP-1，IGFBP-2和IGFBP-3，在PAH中下调，它们影响IGF信号，从而调节PH中的细胞表型。
