Mutation and epigenetic modulation of gene expression within plexiform lesions in patients with severe pulmonary hypertension.

摘要

Pulmonary hypertension (PH) is a rare vascular disorder characterized by elevated pulmonary artery pressure leading eventually to right heart failure and death. Pulmonary arteries of patients with severe PH contain intraluminal proliferations of endothelial cells (EC) known as plexiform lesions (plex). We propose that uncontrolled growth and decreased apoptosis of plex EC may be due to genetic mutations and/or silencing within TGF-β Receptor Type II and Bax secondary to epigenetic loss of mismatch repair protein expression. To test this hypothesis, experiments were performed demonstrating altered gene expression of proteins controlling cell growth, death, and DNA repair in plex EC of patients with PH, and further, that this pathophysiological expression results from gene mutation and disruption of epigenetic control mechanisms. This approach is distinct from classical studies linking peripheral pulmonary artery damage and vasoconstriction as causal to PH. The unique findings herein suggest that mutation and silencing of critical regulatory genes represent a molecular pathological mechanism by which EC proliferate and obstruct pulmonary arteries.