BACKGROUND:Pulmonary hypertension, characterized by vascular remodeling, currently lacks curative therapeutic options. The dysfunction of pulmonary artery endothelial cells plays a pivotal role in the initiation and progression of pulmonary hypertension (PH). ErbB3 (human epidermal growth factor receptor 3), also recognized as HER3, is a member of the ErbB family of receptor tyrosine kinases.METHODS:Microarray, immunofluorescence, and Western blotting analyses were conducted to investigate the pathological role of ErbB3. Blood samples were collected for biomarker examination from healthy donors or patients with hypoxic PH. The pathological functions of ErbB3 were further validated in rodents subjected to chronic hypoxia- and Sugen-induced PH, with or without adeno-associated virus-mediated ErbB3 overexpression, systemic deletion, or endothelial cell–specific ErbB3 knockdown. Primary human pulmonary artery endothelial cells and pulmonary artery smooth muscle cells were used to elucidate the underlying mechanisms.RESULTS:ErbB3 exhibited significant upregulation in the serum, lungs, distal pulmonary arteries, and pulmonary artery endothelial cells isolated from patients with PH compared with those from healthy donors. ErbB3 overexpression stimulated hypoxia-induced endothelial cell proliferation, exacerbated pulmonary artery remodeling, elevated systolic pressure in the right ventricle, and promoted right ventricular hypertrophy in murine models of PH. Conversely, systemic deletion or endothelial cell–specific knockout of ErbB3 yielded opposite effects. Coimmunoprecipitation and proteomic analysis identified YB-1 (Y-box binding protein 1) as a downstream target of ErbB3. ErbB3 induced nuclear translocation of YB-1 and subsequently promoted hypoxia-inducible factor 1/2α transcription. A positive loop involving ErbB3-periostin-hypoxia–inducible factor 1/2α was identified to mediate the progressive development of this disease. MM-121, a human anti-ErbB3 monoclonal antibody, exhibited both preventive and therapeutic effects against hypoxia-induced PH.CONCLUSIONS:Our study reveals, for the first time, that ErbB3 serves as a novel biomarker and a promising target for the treatment of PH.

中文翻译：

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ErbB3 控制缺氧性肺动脉高压中的内皮功能障碍

背景：肺动脉高压以血管重塑为特征，目前缺乏有效的治疗方案。肺动脉内皮细胞功能障碍在肺动脉高压（PH）的发生和进展中起着关键作用。ErbB3（人表皮生长因子受体3），也称为HER3，是受体酪氨酸激酶ErbB家族的成员。方法：采用微阵列、免疫荧光和Western blotting分析研究ErbB3的病理作用。从健康捐献者或缺氧 PH 患者身上采集血液样本进行生物标志物检查。ErbB3 的病理功能在遭受慢性缺氧和 Sugen 诱导的 PH 的啮齿动物中得到进一步验证，无论有或没有腺相关病毒介导的 ErbB3 过表达、系统性缺失或内皮细胞特异性 ErbB3 敲低。使用人原代肺动脉内皮细胞和肺动脉平滑肌细胞来阐明其潜在机制。结果：与PH患者相比，ErbB3在PH患者的血清、肺、远端肺动脉和肺动脉内皮细胞中表现出显着上调。健康的捐赠者。在 PH 小鼠模型中，ErbB3 过表达会刺激缺氧诱导的内皮细胞增殖，加剧肺动脉重塑，升高右心室收缩压，并促进右心室肥厚。相反，系统性缺失或内皮细胞特异性敲除 ErbB3 会产生相反的效果。免疫共沉淀和蛋白质组分析确定 YB-1（Y-box 结合蛋白 1）是 ErbB3 的下游靶标。ErbB3 诱导 YB-1 核转位，随后促进缺氧诱导因子 1/2α 转录。确定了涉及 ErbB3-骨膜素-缺氧-诱导因子 1/2α 的正环路可介导该疾病的进行性发展。MM-121 是一种人源抗 ErbB3 单克隆抗体，对缺氧引起的 PH 具有预防和治疗作用。 结论：我们的研究首次表明，ErbB3 可作为一种新型生物标志物和治疗缺氧性PH的有希望的靶点。 PH值。