Nies Melanie K, Yang Jun, Griffiths Megan, Damico Rachel, Zhu Jie, Vaydia Dhananjay, Fu Zongming, Brandal Stephanie, Austin Eric D, Ivy Dunbar D, Hassoun Paul M, Van Eyk Jennifer E, Everett Allen D
Department of Pediatrics, Division of Cardiology Johns Hopkins University Baltimore Maryland USA.
Department of Pediatrics, Division of Pediatric Cardiology Columbia University New York New York USA.
Pulm Circ. 2022 Apr 20;12(2):e12039. doi: 10.1002/pul2.12039. eCollection 2022 Apr.
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by sustained elevations of pulmonary artery pressure. To date, we lack circulating, diagnostic, and prognostic markers that correlate to clinical and functional parameters. In this study, we performed mass spectrometry-based proteomics analysis to identify circulating biomarkers of PAH. Plasma samples from patients with idiopathic pulmonary arterial hypertension (IPAH, = 9) and matched normal controls ( = 9) were digested with trypsin and analyzed using data-dependent acquisition on an Orbitrap mass spectrometer. A total of 826 (false discovery rate [FDR] 0.047) and 461 (FDR 0.087) proteins were identified across all plasma samples obtained from IPAH and control subjects, respectively. Of these, 153 proteins showed >2 folds change ( < 0.05) between groups. Circulating levels of carbonic anhydrase 2 (CA2), plasma kallikrein (KLKB1), and the insulin-like growth factor binding proteins (IGFBP1-7) were quantified by immunoassay in an independent verification cohort ( = 36 PAH and = 35 controls). CA2 and KLKB1 were significantly different in PAH versus control but were not associated with any functional or hemodynamic measurements. Whereas, IGFBP1 and 2 were associated with higher pulmonary vascular resistance, IGFBP2, 4, and 7 with decreased 6-min walk distance (6MWD), and IGFBP1, 2, 4, and 7 with worse survival. This plasma proteomic discovery analysis suggests the IGF axis may serve as important new biomarkers for PAH and play an important role in PAH pathogenesis.
肺动脉高压（PAH）是一种以肺动脉压力持续升高为特征的进行性疾病。迄今为止，我们缺乏与临床和功能参数相关的循环、诊断和预后标志物。在本研究中，我们进行了基于质谱的蛋白质组学分析，以鉴定PAH的循环生物标志物。对特发性肺动脉高压（IPAH，n = 9）患者和匹配的正常对照（n = 9）的血浆样本进行胰蛋白酶消化，并使用轨道阱质谱仪上的数据依赖采集进行分析。在从IPAH和对照受试者获得的所有血浆样本中，分别鉴定出826种（错误发现率[FDR] 0.047）和461种（FDR 0.087）蛋白质。其中，153种蛋白质在两组之间显示出>2倍的变化（P < 0.05）。通过免疫测定在一个独立的验证队列（n = 36例PAH和n = 35例对照）中对碳酸酐酶2（CA2）、血浆激肽释放酶（KLKB1）和胰岛素样生长因子结合蛋白（IGFBP1 - 7）的循环水平进行了定量。CA2和KLKB1在PAH与对照之间存在显著差异，但与任何功能或血流动力学测量均无关联。而IGFBP1和2与较高的肺血管阻力相关，IGFBP2、4和7与6分钟步行距离（6MWD）降低相关，IGFBP1、2、4和7与较差的生存率相关。这项血浆蛋白质组学发现分析表明，IGF轴可能作为PAH重要的新生物标志物，并在PAH发病机制中发挥重要作用。
