Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, CA 94305, USA.
Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University, Stanford, CA 94305, USA.
Cells. 2023 Jan 14;12(2):316. doi: 10.3390/cells12020316.
Bone morphogenic protein receptor 2 (BMPR2) expression and signaling are impaired in pulmonary arterial hypertension (PAH). How BMPR2 signaling is decreased in PAH is poorly understood. Protein tyrosine phosphatases (PTPs) play important roles in vascular remodeling in PAH. To identify whether PTPs modify BMPR2 signaling, we used a siRNA-mediated high-throughput screening of 22,124 murine genes in mouse myoblastoma reporter cells using ID1 expression as readout for BMPR2 signaling. We further experimentally validated the top hit, PTPN1 (PTP1B), in healthy human pulmonary arterial endothelial cells (PAECs) either silenced by siRNA or exposed to hypoxia and confirmed its relevance to PAH by measuring PTPN1 levels in blood and PAECs collected from PAH patients. We identified PTPN1 as a novel regulator of BMPR2 signaling in PAECs, which is downregulated in the blood of PAH patients, and documented that downregulation of PTPN1 is linked to endothelial dysfunction in PAECs. These findings point to a potential involvement for PTPN1 in PAH and will aid in our understanding of the molecular mechanisms involved in the disease.
骨形态发生蛋白受体 2（BMPR2）的表达和信号在肺动脉高压（PAH）中受损。PAH 中 BMPR2 信号如何降低仍知之甚少。蛋白酪氨酸磷酸酶（PTPs）在 PAH 中的血管重构中发挥重要作用。为了确定 PTPs 是否修饰 BMPR2 信号，我们使用基于 ID1 表达的报告细胞，通过 siRNA 介导的高通量筛选了 22124 种小鼠基因，作为 BMPR2 信号的读出。我们进一步在健康人肺动脉内皮细胞（PAECs）中通过 siRNA 沉默或暴露于低氧条件下对排名最高的候选基因 PTPN1（PTP1B）进行了实验验证，并通过测量来自 PAH 患者的血液和 PAECs 中的 PTPN1 水平，证实了其与 PAH 的相关性。我们鉴定出 PTPN1 是 PAECs 中 BMPR2 信号的新型调节剂，在 PAH 患者的血液中下调，并记录到 PTPN1 的下调与 PAECs 中的内皮功能障碍有关。这些发现表明 PTPN1 可能参与了 PAH，并将有助于我们理解该疾病涉及的分子机制。
