Serum proteome profiling reveals HGFA as a candidate biomarker for pulmonary arterial hypertension.

IF 5.8 2区医学 Q1 Medicine

Respiratory Research Pub Date : 2024-11-28 DOI:10.1186/s12931-024-03036-1

Meng Zhang, Haobo Li, Shuangshuang Ma, Xincheng Li, Linfeng Xi, Yishan Li, Zhu Zhang, Shuai Zhang, Qian Gao, Qiang Huang, Jun Wan, Wanmu Xie, Jifeng Li, Peiran Yang, Yunxia Zhang, Zhenguo Zhai

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引用次数: 0

Abstract

Background: Identification and validation of potential biomarkers could facilitate the identification of pulmonary arterial hypertension (PAH) and thus aid to study their roles in the disease process.

Methods: We used the isobaric tag for relative and absolute quantitation approaches to compare the protein profiles between the serum of PAH patients and the controls. Bioinformatics analyses and enzyme-linked immunosorbent assay (ELISA) identification of PAH patients and the controls were performed to identify the potential biomarkers. The receiver operating characteristic curve (ROC) analysis was used to evaluate the diagnostic performance of these potential biomarkers. Mendelian randomization (MR) analysis further clarified the relationship between the potential biomarkers and PAH. Additionally, the expression levels of the potential biomarkers were further validated in two PAH animal models (monocrotaline-PH and Sugen5416 plus hypoxia-PH) using ELISA and reverse transcription-quantitative PCR (RT-qPCR).

Results: We identified significant changes in three proteins including heparanase (HPSE), gelsolin (GSN), and hepatocyte growth factor activator (HGFA) in PAH patients. The ROC analysis showed that the areas under the curve of HPSE, GSN, and HGFA in differentiating PAH patients from controls were 0.769, 0.777, and 0.964, respectively. HGFA was correlated with multiple parameters of right ventricular functions in PAH patients. Besides proteomic analysis, we also used MR method to demonstrate the causal link between genetically reduced HGFA levels and an increased risk of PAH. In subsequent validation study in PAH animal models, the mRNA expression levels of HGFA in the lung tissues were significantly lower in PAH rat models than in controls. In the rat models, serum levels of HGFA were lower compared to the control group and showed a negative correlation with right ventricular systolic pressure.

Conclusion: The study demonstrated that HGFA might be a promising biomarker for noninvasive detection of PAH.

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血清蛋白质组分析显示HGFA是肺动脉高压的候选生物标志物。

背景：潜在生物标志物的鉴定和验证有助于肺动脉高压（PAH）的识别，从而有助于研究它们在疾病过程中的作用。方法：采用等压标记法进行相对定量和绝对定量，比较PAH患者与对照组血清蛋白谱。对PAH患者和对照组进行生物信息学分析和酶联免疫吸附试验（ELISA）鉴定，以确定潜在的生物标志物。采用受试者工作特征曲线（ROC）分析评价这些潜在生物标志物的诊断性能。孟德尔随机化（MR）分析进一步阐明了潜在生物标志物与多环芳烃之间的关系。此外，利用ELISA和逆转录定量PCR （RT-qPCR）进一步验证了两种PAH动物模型（monocrotaline-PH和Sugen5416 + hypoxia-PH）中潜在生物标志物的表达水平。结果：我们在PAH患者中发现了肝素酶（HPSE）、凝胶蛋白（GSN）和肝细胞生长因子激活剂（HGFA）三种蛋白的显著变化。ROC分析显示，HPSE、GSN、HGFA对PAH患者与对照组的鉴别曲线下面积分别为0.769、0.777、0.964。HGFA与PAH患者右心室功能多项参数相关。除了蛋白质组学分析，我们还使用MR方法来证明遗传降低的HGFA水平与PAH风险增加之间的因果关系。在随后的PAH动物模型验证研究中，PAH模型大鼠肺组织中HGFA mRNA表达水平明显低于对照组。在大鼠模型中，血清HGFA水平低于对照组，且与右心室收缩压呈负相关。结论：HGFA可能是一种有前途的无创检测PAH的生物标志物。

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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来源期刊

Respiratory Research RESPIRATORY SYSTEM-

CiteScore

9.70

自引率

1.70%

发文量

314

审稿时长

4-8 weeks

期刊介绍： Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.