Hua Mao, Claire M Li, Bing Sun, Christopher Ward, Alan Waich-Cohen, Ivan O Rosas, Howard J Huang, Harry Karmouty-Quintana, Liang Xie, Lavannya M Pandit, Xinchun Pi
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引用次数: 0
Abstract
Background: BMPER (bone morphogenetic protein-binding endothelial regulator) is a secreted protein that is highly expressed in endothelial cells. It regulates the BMP (bone morphogenetic protein) pathway during vascular development and adulthood. Mutations in the BMP pathway are recognized as risk factors for pulmonary arterial hypertension group 1 pulmonary hypertension (PH). However, the roles of BMPER in pulmonary arterial hypertension remain unknown.
Methods: We assessed BMPER expression in Group 1 pulmonary arterial hypertension patient samples and examined its role in vascular remodeling using in vivo and in vitro approaches.
Results: BMPER level was elevated in pulmonary arterial hypertension lungs and significantly associated with pulmonary vascular resistance, but was not increased in patient plasma. Global and endothelial cell-specific depletion of BMPER in a mouse model of hypoxia-induced PH displayed attenuation in pulmonary artery smooth muscle cell proliferation, a hallmark of pulmonary vascular remodeling, and reduced right ventricular pressures. Conversely, adeno-associated virus-assisted BMPER overexpression targeted to the pulmonary endothelium led to the spontaneous development of PH. Mechanistically, BMPER promoted YAP (yes-associated protein 1) activation through the release of YAP sequestration by LRP1 (low-density lipoprotein receptor-related protein 1), a BMPER endocytic receptor, in the membrane of pulmonary artery smooth muscle cells. Moreover, the protective effect of BMPER depletion can be reversed by simultaneous depletion of LRP1 in mice with hypoxia-induced PH.
Conclusions: Collectively, these results implicate secreted BMPER as a discrete regulator for pulmonary vascular remodeling and suggest its inhibition as a new potential therapeutic strategy against PH.
背景:骨形态发生蛋白结合内皮调节因子(BMPER)是一种在内皮细胞中高表达的分泌蛋白。它在血管发育和成年期调节BMP(骨形态发生蛋白)通路。BMP通路突变被认为是肺动脉高压(PH)的危险因素。然而,BMPER在肺动脉高压中的作用尚不清楚。方法:我们通过体内和体外方法检测BMPER在1组肺动脉高压患者样本中的表达,并研究其在血管重构中的作用。结果:BMPER水平在肺动脉高压肺中升高,且与肺血管阻力显著相关,但在血浆中未升高。在缺氧诱导的PH小鼠模型中,BMPER的整体和内皮细胞特异性耗竭显示肺动脉平滑肌细胞增殖的衰减,这是肺血管重构的标志,并降低了右心室压力。相反,腺相关病毒辅助的针对肺内皮的BMPER过表达导致ph的自发发展。从机制上讲,BMPER通过肺动脉平滑肌细胞膜中的BMPER内吞受体LRP1(低密度脂蛋白受体相关蛋白1)释放YAP (ye -associated protein 1)来促进YAP (ye -associated protein 1)的激活。此外,在缺氧诱导PH小鼠中,BMPER耗竭的保护作用可以通过同时耗竭LRP1而逆转。结论:总的来说,这些结果表明分泌的BMPER是肺血管重塑的一个独立调节剂,并表明抑制BMPER是一种新的潜在的治疗PH的策略。
期刊介绍:
The journal "Arteriosclerosis, Thrombosis, and Vascular Biology" (ATVB) is a scientific publication that focuses on the fields of vascular biology, atherosclerosis, and thrombosis. It is a peer-reviewed journal that publishes original research articles, reviews, and other scholarly content related to these areas. The journal is published by the American Heart Association (AHA) and the American Stroke Association (ASA).
The journal was published bi-monthly until January 1992, after which it transitioned to a monthly publication schedule. The journal is aimed at a professional audience, including academic cardiologists, vascular biologists, physiologists, pharmacologists and hematologists.