Pulmonary artery proteomic profiles distinguish PAH-SSc from SSc, revealing TGFβI/ig-h3 downregulation

Pulmonary Arterial Hypertension associated with Systemic Sclerosis (PAH-SSc) is a severe and life-threatening complication of Systemic Sclerosis (SSc), characterized by progressive pulmonary vascular remodeling and right ventricular failure. Early diagnosis and effective therapeutic targets remain challenging, as current diagnostic methods and risk stratification tools are often insufficient. Proteomic analysis offers a powerful approach to identify novel biomarkers and understand underlying disease mechanisms by comprehensively profiling protein expression. Investigating the transpulmonary proteomic gradient and comparing profiles between PAH-SSc and SSc patients could reveal unique insights into local pulmonary vascular pathology and systemic disease interactions, addressing a critical gap in understanding this complex condition.

This study analyzed proteomic alterations in the pulmonary circulation of 20 women (10 with PAH-SSc, 10 with SSc without PAH) aged 62.8-64.6 years. The transpulmonary gradient was assessed by comparing biomarker concentrations between wedge-position and pulmonary artery blood samples. Peptides were extracted and analyzed using liquid chromatography-mass spectrometry (LC-MS). Differentially abundant proteins were identified using Proteome Discoverer software. Protein-protein interaction networks were generated with STRING and visualized in Cytoscape to explore functional relationships among the identified proteins, comparing the distinct proteomic profiles between the two patient groups.

A total of 270 proteins were detected across all samples. Interestingly, the study found no significant transpulmonary gradient alterations in protein concentrations between wedge-position and pulmonary artery blood samples. However, patients with PAH-SSc exhibited distinct proteomic profiles compared to those with SSc without PAH. Multivariate analysis identified 48 differentially abundant proteins in pulmonary artery plasma between the two groups. Of these, 15 proteins were overrepresented and 33 proteins were downregulated in PAH-SSc patients. The most notable finding was:

The significant downregulation of transforming growth factor-beta-induced protein ig-h3 (TGFβI/ig-h3) in PAH-SSc patients, strongly suggesting a potential involvement of the TGF-β-related extracellular matrix remodeling pathway in the disease pathogenesis. Beyond TGFβI/ig-h3, the distinct proteomic profile in PAH-SSc was also characterized by differences in proteins associated with immune response, lipid metabolism, and hemostatic processes, highlighting multifaceted pathological changes.