HIMF (Hypoxia-Induced Mitogenic Factor) Signaling Mediates the HMGB1 (High Mobility Group Box 1)-Dependent Endothelial and Smooth Muscle Cell Crosstalk in Pulmonary Hypertension
HIMF (Hypoxia-Induced Mitogenic Factor) Signaling Mediates the HMGB1 (High Mobility Group Box 1)-Dependent Endothelial and Smooth Muscle Cell Crosstalk in Pulmonary Hypertension
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DOI：
10.1161/atvbaha.119.312907
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发表时间：
2019-12-01
影响因子：
8.7
通讯作者：
Johns, Roger A.
中科院分区：
文献类型：
--
作者：
Lin, Qing;Fan, Chunling;Johns, Roger A.
目的：低氧诱导的有丝分裂因子(HIMF)又称FIZZ1[发现于炎症区-1]或RELM[Resisin-like Molecules-α]，是啮齿动物肺动脉高压的病因学因素，但其作用机制尚不清楚。我们研究了HIF信号在PH发病机制中的免疫调节特性。方法和结果：体内实验采用缺乏Himf基因(KO[基因敲除])或过表达Himf人类同源抵抗素(HResistin)的转基因小鼠。在慢性低氧或SUGEN/低氧暴露的HIMF-KO小鼠中，证实了HIMF的促PH作用。在体内低氧小鼠肺内皮细胞和体外培养的人肺微血管内皮细胞中，HIMF/hResistin的激活触发了HMGB1(高迁移率族蛋白1)途径和RAGE(晚期糖基化终产物受体)。HResistin刺激的人肺微血管内皮细胞的条件培养液以HMGB1依赖的方式诱导人肺微血管内皮细胞的自噬反应、骨形态发生蛋白受体2(BMPR2)缺陷以及随后的抗凋亡增殖。这些效应在特发性肺高压患者的肺血管内皮细胞和平滑肌细胞中得到证实。Himf/HMGB1/RAGE介导的自噬和BMPR2损伤也出现在低氧小鼠的肺动脉(血管)平滑肌细胞中，其作用可能与Himf抑制FoxO1(叉头盒O1)有关。在EC特异性hResistin过表达转基因小鼠中的实验证实，EC来源的HMGB1介导了hResistin驱动的肺血管重构和PH。结论：在HIMF诱导的肺动脉高压中，HMGB1-RAGE信号在介导EC-平滑肌细胞串扰中起关键作用。人源化的小鼠数据进一步支持HIMF/HMGB1信号轴的临床意义，并表明hResistin及其下游途径可能成为人类抗PH新药开发的靶点。
Objective: HIMF (hypoxia-induced mitogenic factor; also known as FIZZ1 [found in inflammatory zone-1] or RELM [resistin-like molecule-alpha]) is an etiological factor of pulmonary hypertension (PH) in rodents, but its underlying mechanism is unclear. We investigated the immunomodulatory properties of HIMF signaling in PH pathogenesis. Approach and Results: Gene-modified mice that lacked HIMF (KO [knockout]) or overexpressed HIMF human homolog resistin (hResistin) were used for in vivo experiments. The pro-PH role of HIMF was verified in HIMF-KO mice exposed to chronic hypoxia or sugen/hypoxia. Mechanistically, HIMF/hResistin activation triggered the HMGB1 (high mobility group box 1) pathway and RAGE (receptor for advanced glycation end products) in pulmonary endothelial cells (ECs) of hypoxic mouse lungs in vivo and in human pulmonary microvascular ECs in vitro. Treatment with conditioned medium from hResistin-stimulated human pulmonary microvascular ECs induced an autophagic response, BMPR2 (bone morphogenetic protein receptor 2) defects, and subsequent apoptosis-resistant proliferation in human pulmonary artery (vascular) smooth muscle cells in an HMGB1-dependent manner. These effects were confirmed in ECs and smooth muscle cells isolated from pulmonary arteries of patients with idiopathic PH. HIMF/HMGB1/RAGE-mediated autophagy and BMPR2 impairment were also observed in pulmonary artery (vascular) smooth muscle cells of hypoxic mice, effects perhaps related to FoxO1 (forkhead box O1) dampening by HIMF. Experiments in EC-specific hResistin-overexpressing transgenic mice confirmed that EC-derived HMGB1 mediated the hResistin-driven pulmonary vascular remodeling and PH. Conclusions: In HIMF-induced PH, HMGB1-RAGE signaling is pivotal for mediating EC-smooth muscle cell crosstalk. The humanized mouse data further support clinical implications for the HIMF/HMGB1 signaling axis and indicate that hResistin and its downstream pathway may constitute targets for the development of novel anti-PH therapeutics in humans.