Heterogeneous nuclear ribonucleoprotein A1 as a candidate associated with pulmonary vascular remodeling in pulmonary arterial hypertension.

Rationale: Although plexiform lesion (PL) formation in severe pulmonary arterial hypertension (PAH) is a therapeutic target, the mechanisms underlying their formation have not been fully elucidated. Objective: To identify candidate proteins involved in PL formation by examining differentially expressed proteins (DEPs) in PAH lesions. Methods: Proteomic remodeling was assessed before and after the formation of PLs in a SU5416 combined with hypoxia (SuHx) rat model of severe PAH using laser-capture microdissection coupled with mass spectrometry. Unobstructed pulmonary arteries with medial hypertrophy (UMHPAs) and PLs from SuHx rats were subjected to qualitative and quantitative proteomics, revealing DEPs between these structures. Results: We identified 718 proteins with 58 DEPs, of which 31 were upregulated in UMHPAs and 27 were upregulated in PLs. Immunostaining confirmed that DEPs detected in our proteomic analysis were differentially expressed between UMHPAs and PLs. Among them, we focused on heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) as a candidate protein that may be associated with PL formation because of its strong association with cell proliferation. Small interfering RNA knockdown of hnRNPA1 in hypoxia-treated pulmonary artery smooth muscle cells reduced pyruvate kinase M2 expression and decreased proliferative capacity. Conclusions: Several DEPs associated with PL formation but with unclear relevance to pulmonary artery remodeling in PAH were discovered. Among these, hnRNPA1, which was not detected in transcriptome analysis and whole lung analysis, may be important in PL formation.