Multi-Omics Analysis of the PDGF Response in Pulmonary Vascular Smooth Muscle Cells from Patients with Pulmonary Arterial Hypertension: Implication of the NMDAR

F. Akoumia
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Abstract

Multi-Omics Analysis of the PDGF Response in Pulmonary Vascular Smooth Muscle Cells from Patients with Pulmonary Arterial Hypertension: Implication of the NMDAR The N-methyl-D-aspartate receptor (NMDAR), expressed by PASMC, has been pointed as a novel therapeutic target in PAH, and is a new player involved in the PDGF-dependent proliferation of PASMC. Decoding the mechanisms of action of NMDAR antagonist is important to validate it as a therapeutic option in PAH. Multi-omics approach was designed to study the transcriptional and translational response to PDGF, with or without NMDAR blockade, in PASMC of PAH patients. PASMC of PAH patients and controls in culture were stimulated with PDGF-BB 10 μM for 24 h and exposed to 100 μM MK-801, a noncompetitive NMDAR antagonist. The transcriptomic analysis was done on a Microarray Scanner DNA chip. Proteomic analysis was done using a high resolution Orbitrap mass spectrometer. Transcriptomics revealed that PDGF induced the expression of genes involved in proliferation, migration and apoptosis resistance in PASMC. Exposure to MK-801 reversed these effects. Proteomics revealed 748 differentially expressed proteins between patient and control PASMC, and highlighted overexpression of a large number of members of the Rab protein family. Their expression was increased in patient PASMC exposed to PDGF and was decreased by MK-801 treatment. Consistent with transcriptomics, PDGF induced pro-proliferative proteins while MK-801 induced anti-proliferative proteins in PASMCs of PAH patients. Multi-omics analysis showed that PDGF induced pro-proliferative gene and protein expression tended to normalize using NMDAR in PASMC. These results further support NMDARs as a therapeutic target for the treatment of PAHs.
肺动脉高压患者肺血管平滑肌细胞PDGF反应的多组学分析:NMDAR的意义
由PASMC表达的n -甲基-d -天冬氨酸受体(NMDAR)已被认为是PAH的新治疗靶点,并且是参与PDGF依赖性PASMC增殖的新参与者。解码NMDAR拮抗剂的作用机制对于验证其作为PAH的治疗选择非常重要。多组学方法旨在研究PDGF在PAH患者PASMC中有或没有NMDAR阻断的转录和翻译反应。用10 μM的PDGF-BB刺激PAH患者和对照组的PASMC 24 h,并暴露于100 μM的MK-801(一种非竞争性NMDAR拮抗剂)。转录组分析在微阵列扫描DNA芯片上完成。蛋白质组学分析使用高分辨率Orbitrap质谱仪进行。转录组学结果显示,PDGF诱导PASMC中参与增殖、迁移和抗凋亡的基因表达。暴露于MK-801中可以逆转这些影响。蛋白质组学显示,PASMC患者与对照组之间存在748个差异表达蛋白,并强调了Rab蛋白家族大量成员的过表达。它们的表达在暴露于PDGF的PASMC患者中增加,而在MK-801治疗中降低。与转录组学一致,PDGF诱导PAH患者PASMCs中促增殖蛋白,而MK-801诱导抗增殖蛋白。多组学分析显示,PDGF诱导PASMC中促增殖基因和蛋白的表达趋于正常化。这些结果进一步支持NMDARs作为治疗多环芳烃的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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