IL-33 Initiates Vascular Remodelling in Hypoxic Pulmonary Hypertension by up-Regulating HIF-1α and VEGF Expression in Vascular Endothelial Cells.
IL-33 Initiates Vascular Remodelling in Hypoxic Pulmonary Hypertension by up-Regulating HIF-1α and VEGF Expression in Vascular Endothelial Cells.
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IL-33 通过上调血管内皮细胞中 HIF-1 α 和 VEGF 的表达来启动缺氧性肺动脉高压的血管重塑
DOI：
10.1016/j.ebiom.2018.06.003
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发表时间：
2018-07
期刊：
影响因子：
11.1
通讯作者：
Wang C
中科院分区：
文献类型：
--
作者：
Liu J;Wang W;Wang L;Chen S;Tian B;Huang K;Corrigan CJ;Ying S;Wang W;Wang C
IL-33可能在低氧性肺动脉高压（PH）的血管重构中发挥作用，但其确切机制尚不清楚。我们假设缺氧促进血管内皮细胞IL-33及其受体ST2的表达，从而导致血管内皮细胞和平滑肌细胞功能障碍，从而导致PH升高。免疫组织化学显示，缺氧诱导PH （HPH）小鼠模型和支气管扩张-PH受试者肺组织中IL-33和ST2的免疫反应性显著升高。经胸超声心动图显示，与WT小鼠相比，St2−/−小鼠与HPH相关的血流动力学改变和右心室肥厚明显消失。在缺氧暴露的WT小鼠中，给予IL-33进一步加剧了这些变化。在体外，缺氧显著提高人肺动脉内皮细胞（HPAECs） IL-33/ST2的表达，外源性IL-33增强HPAECs的增殖、粘附性和自发血管生成。使用siRNA转染敲低内源性Il33或St2在常氧和缺氧培养条件下均可显著抑制这些作用。St2基因的缺失减弱了缺氧诱导的HIF-1α/VEGFA/VEGFR-2/ICAM-1的肺表达升高，而外源性VEGFA的管理部分逆转了ph的血流动力学指标的衰减。相应地，St2或Hif1α基因的敲低几乎完全消除了il -33诱导的HIF-1α/VEGFA/VEGFR-2的体外hpaec表达。此外，通过敲低Hif1α/Vegfa或Vegfr2基因，il -33诱导的HPAECs血管生成被广泛消除。这些数据表明，缺氧诱导HPAECs IL-33/ST2表达升高，至少部分原因是HIF-1α和VEGF的下游表达增加，引发血管重构，导致HPH。长期以来，我们一直关注细胞因子在慢性肺部疾病发病机制中的作用，包括哮喘、COPD、纤维化和支气管扩张。我们等人发现IL-33可能通过与其受体ST2结合参与许多其他疾病的发生和预后。基于这些发现，我们非常渴望知道IL-33/ST2轴是否也在缺氧诱导的肺动脉高压（HPH）中发挥作用，HPH是许多慢性呼吸系统疾病的并发症。虽然已知HIF-1α和VEGF在该并发症中起关键作用，但HIF-1α和VEGF的上游是什么尚不清楚。因此，我们首先测试了IL-33及其受体ST2在手术标本和我们建立的小鼠HPH模型中肺组织切片中的免疫反应性。令人惊讶的是，我们注意到在这些组织切片中，这两个目标的免疫反应性都增加了。这些发现启发我们进一步探索IL-33/ST2在HPH发病机制中的细节。由于缺乏有效的治疗，HPH是一种危及生命的并发症。虽然肺动脉和心室重构可能是该病的主要发病机制，但其确切机制在很大程度上尚不清楚。在本研究中，我们发现缺氧是内皮细胞诱导IL-33和ST2表达的关键驱动因素。这些因子依次触发内皮细胞表达HIF-1α和VEGF，导致内皮细胞增殖、粘附和成管。我们还发现，在IL-33存在的情况下，内皮细胞能够影响动脉平滑肌细胞的增殖和迁移，尽管单独IL-33没有这种影响。这些发现提示缺氧和IL-33/ST2可能通过调控下游因子HIF-1α和VEGF成为HPH的启动因子。我们的数据表明，IL-33/ST2轴在缺氧诱导的肺动脉高压的发病机制中起着关键作用，因为这些分子的消耗在很大程度上缓解了并发症的现象。这些观察结果可能为HPH的临床治疗提供替代的治疗策略。
IL-33 may play a role in the vascular remodelling of hypoxic pulmonary hypertension (PH) but the precise mechanisms are still unclear. We hypothesized that hypoxia promotes expression of IL-33 and its receptor ST2 on vascular endothelial cells, which in turn leads to dysfunction of vascular endothelial cells and smooth muscle cells contributing to PH. Immunohistochemistry showed that immunoreactivity for IL-33 and ST2 was significantly increased in lung tissue of murine model of hypoxia-induced PH (HPH) and of subjects with bronchiectasis-PH. trans-Thoracic echocardiography showed that haemodynamic changes and right ventricular hypertrophy associated with HPH were significantly abrogated in St2−/− compared with WT mice. Administration of IL-33 further exacerbated these changes in the hypoxia-exposed WT mice. In vitro, hypoxia significantly increased IL-33/ST2 expression by human pulmonary arterial endothelial cells (HPAECs), while exogenous IL-33 enhanced proliferation, adhesiveness and spontaneous angiogenesis of HPAECs. Knockdown of endogenous Il33 or St2 using siRNA transfection significantly suppressed these effects in both normoxic and hypoxic culture-conditions. Deletion of the St2 gene attenuated hypoxia-induced, elevated lung expression of HIF-1α/VEGFA/VEGFR-2/ICAM-1, while administration of exogenous VEGFA partially reversed the attenuation of the haemodynamic indices of PH. Correspondingly, knockdown of the St2 or Hif1α genes almost completely abrogated IL-33-induced expression of HIF-1α/VEGFA/VEGFR-2 by HPAECs in vitro. Further, IL-33-induced angiogenesis by HPAECs was extensively abrogated by knockdown of the Hif1α/Vegfa or Vegfr2 genes. These data suggest that hypoxia induces elevated expression of IL-33/ST2 by HPAECs which, at least partly by increasing downstream expression of HIF-1α and VEGF initiates vascular remodelling resulting in HPH. Evidence before this study We have been focusing on the role of cytokines in the pathogenesis of chronic pulmonary diseases for a long time, including asthma, COPD, fibrosis and bronchiectasis. We and others found that IL-33 might contribute to the occurrence and prognosis of many other diseases through binding its receptor ST2. Based on these findings, we were very eager to know whether IL-33/ST2 axis also exerts a role in hypoxia-induced pulmonary hypertension (HPH), a complication of many chronic respiratory diseases. Although it is well known that HIF-1α and VEGF play critical role in this complication, it is still unclear what the upstream of HIF-1α and VEGF is. Therefore, we first tested immunoreactivity for IL-33 and its receptor ST2 in the lung tissue sections derived from surgical specimens and from our established murine models of HPH. Surprisingly, we noted the increased immunoreactivity for both targets in these tissue sections. These findings inspired us to further explore the details of IL-33/ST2 in the pathogenesis of HPH. Added value of this study HPH is a life-threatening complication because there is lack of effective treatment. Although pulmonary arteries and ventricular remodelling might be mainly involved in the pathogenesis of the disease, the precise mechanisms are largely unknown. In the present study, we showed that hypoxia is a critical driver which induced expression of IL-33 and ST2 by endothelial cells. These factors, in turn triggered expression of HIF-1α and VEGF by endothelial cells and led to proliferation, adhesion and tube formation of these cells. We also showed that in the presence of IL-33, endothelial cells were able to affect proliferation and migration of artery smooth muscle cells, although IL-33 alone did not have such effects. These findings suggest that hypoxia and IL-33/ST2 might be initiators for HPH, through regulating downstream factors HIF-1α and VEGF. Implications of all the available evidence Our data suggest that IL-33/ST2 axis plays critical role in the pathogenesis of hypoxia-induced pulmonary hypertension because depletion of these molecules much remitted the phenomenon of complication. These observations might provide alternative therapeutic strategy for clinical treatment of HPH.
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影响因子：
4.6
作者：
Stojkovic S;Kaun C;Basilio J;Rauscher S;Hell L;Krychtiuk KA;Bonstingl C;de Martin R;Gröger M;Ay C;Holnthoner W;Eppel W;Neumayer C;Huk I;Huber K;Demyanets S;Wojta J
通讯作者：
Wojta J
影响因子：
21.3
作者：
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通讯作者：
Dimmeler, Stefanie
影响因子：
24.1
作者：
通讯作者：
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影响因子：
3.6
作者：
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通讯作者：
Ayala, Fabio
DOI：
10.1161/atvbaha.115.306710
发表时间：
2016-01
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Johns RA;Takimoto E;Meuchel LW;Elsaigh E;Zhang A;Heller NM;Semenza GL;Yamaji-Kegan K
通讯作者：
Yamaji-Kegan K