Abstract
Introduction: Pulmonary arterial hypertension (PAH) is a relative common complication in patients with congenital heart disease (CHD), affecting both disease progression and prognosis. The pathogenic mechanisms that lead to “irreversible” PAH are therefore poorly understood in subjects with CHD. Hypothesis: The aim of this study was to apply proteomics to discover protein regulations in the lungs of irreversible PAH patients, which could lead to generation of new hypotheses concerning signaling pathways and elucidating the pathophysiology of irreversible PAH. Methods: Label-free liquid chromatography tandem mass spectrometry was used to compare protein profiles in surgical samples of lungs from 4 patients with irreversible CHD-PAH, 4 reversible CHD-PAH and 4 control subjects. Result: A total of 133 proteins were differently expressed. The majority of differential expressed proteins were associated with cytoskeleton remodeling, integrin-mediated cell adhesion and migration, endothelial cell contacts, blood coagulation and HDL-mediated reverse cholesterol transport. Novel findings included increased expression of filamin A and caveolin-1 and decreased expression of glutathione S-transferase (GST) family. Filamin A, a major isoform of the filamin family which is a family of cytoskeletal proteins that have been implicated as critical mediators of organ development and cell signaling and migration. In the present study, the density and cellular location of filamin A immunoreactivity was accordant with caveolin-1. The results were confirmed by Western blot and immunohistochemistry. In reversible CHD-PAH and control lung tissue, filamin A and caveolin-1 were prominent in endothelium of pulmonary arteriole. In irreversible CHD-PAH lung tissue, they were prominent in the vascular smooth muscle cell. Conclusions: Label-free proteomics identified differences in the expression of several proteins in the CHD-PAH lung, many of which are relevant to the cell proliferation, differentiation and migration. Increased expression of filamin A and caveolin-1 may be pertinent to the proliferation and migration of vascular smooth muscle cell. Decreased expression of GST indicated impaired anti-oxidative function in irreversible CHD-PAH.
Published Version
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