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Background <p>The development of pulmonary hypertension (PH) is a serious complication of chronic obstructive pulmonary disease (COPD). Despite advances in characterizing pulmonary vascular remodeling in COPD-PH, the lack of targeted therapies limits the routine use of gold-standard invasive diagnostics, highlighting the need for novel biomarkers. The pulmonary vascular endothelium is central to the pathogenesis of both PH and COPD. Since most endothelium-derived modulators of vascular tone and remodeling are targets of endothelial-enriched microRNA-126 (miR-126), a master vascular regulator that is suppressed in COPD, these and related ‘angiocentric molecules’ may be promising biomarkers for COPD-PH.</p> Research Goal <p>To identify angiocentric proteins elevated in individuals with suspected COPD-PH, defined by a pulmonary artery-to-aorta ratio (PA/A) &gt; 1 on thoracic CT, and to evaluate if they are significantly associated with the severity of airflow limitation (FEV₁).</p> Study Design <p>We analyzed plasma proteomic profiles from 1,056 COPDGene Phase-1 participants. Using PA/A &gt; 1 as the outcome, we identified differentially abundant angiocentric proteins. We then assessed the abundance of angiocentric proteins in those with severe airflow obstruction (FEV₁ &lt;50% predicted) among both the COPDGene Phase-1 participants and 188 SPIROMICS Visit-1 participants, and validated the findings in an independent cohort of 363 COPDGene Phase-2 participants. Mediation analyses of multi-omic data examined the relationships between specific miR-126-3p and -p strands levels, their target mRNA and protein levels, and the severity of airflow obstruction.</p> Results <p>Seventeen angiocentric proteins were increased in participants with PA/A &gt; 1, with interleukin-1 receptor-like 1 (IL1RL1) and platelet-derived growth factor B (PDGFB) showing the most significant elevations. Among those with FEV₁ &lt;50% predicted, eleven angiocentric proteins were increased, including IL1RL1, angiopoietin-2, and peroxiredoxin-5. Mediation analyses supported a contribution of reduced miR-126 levels to lower FEV₁ via select angiocentric molecules, including the direct miR-126 target selenoprotein T. Additionally, LINC01506 and CAPZA1 had a mediation effect on multiple clinical outcomes, including FEV₁, DLCO, and hematocrit.</p> Conclusion <p>In addition to their role in pulmonary vascular remodeling, miR-126–regulated angiocentric proteins are also linked to airflow limitation, highlighting their potential as candidate biomarkers for COPD-associated pulmonary hypertension.</p>

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Vascular-related proteomic signatures in COPD with suspected pulmonary hypertension as predictors of FEV₁ impairment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月28日

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  • Khushboo Goel,
  • Ryen Ormesher,
  • Katherine A. Pratte,
  • Yue Wang,
  • Koichi Nishino,
  • Craig P. Hersh,
  • Katerina Kechris,
  • Russell P. Bowler,
  • Irina Petrache

摘要

Background

The development of pulmonary hypertension (PH) is a serious complication of chronic obstructive pulmonary disease (COPD). Despite advances in characterizing pulmonary vascular remodeling in COPD-PH, the lack of targeted therapies limits the routine use of gold-standard invasive diagnostics, highlighting the need for novel biomarkers. The pulmonary vascular endothelium is central to the pathogenesis of both PH and COPD. Since most endothelium-derived modulators of vascular tone and remodeling are targets of endothelial-enriched microRNA-126 (miR-126), a master vascular regulator that is suppressed in COPD, these and related ‘angiocentric molecules’ may be promising biomarkers for COPD-PH.

Research Goal

To identify angiocentric proteins elevated in individuals with suspected COPD-PH, defined by a pulmonary artery-to-aorta ratio (PA/A) > 1 on thoracic CT, and to evaluate if they are significantly associated with the severity of airflow limitation (FEV₁).

Study Design

We analyzed plasma proteomic profiles from 1,056 COPDGene Phase-1 participants. Using PA/A > 1 as the outcome, we identified differentially abundant angiocentric proteins. We then assessed the abundance of angiocentric proteins in those with severe airflow obstruction (FEV₁ <50% predicted) among both the COPDGene Phase-1 participants and 188 SPIROMICS Visit-1 participants, and validated the findings in an independent cohort of 363 COPDGene Phase-2 participants. Mediation analyses of multi-omic data examined the relationships between specific miR-126-3p and -p strands levels, their target mRNA and protein levels, and the severity of airflow obstruction.

Results

Seventeen angiocentric proteins were increased in participants with PA/A > 1, with interleukin-1 receptor-like 1 (IL1RL1) and platelet-derived growth factor B (PDGFB) showing the most significant elevations. Among those with FEV₁ <50% predicted, eleven angiocentric proteins were increased, including IL1RL1, angiopoietin-2, and peroxiredoxin-5. Mediation analyses supported a contribution of reduced miR-126 levels to lower FEV₁ via select angiocentric molecules, including the direct miR-126 target selenoprotein T. Additionally, LINC01506 and CAPZA1 had a mediation effect on multiple clinical outcomes, including FEV₁, DLCO, and hematocrit.

Conclusion

In addition to their role in pulmonary vascular remodeling, miR-126–regulated angiocentric proteins are also linked to airflow limitation, highlighting their potential as candidate biomarkers for COPD-associated pulmonary hypertension.