H3K27 histone lysine methylation as potential therapeutic target in pulmonary arterial hypertension

Rationale: Pulmonary arterial hypertension (PAH) is characterized by profound vascular remodeling of small pulmonary arteries that pathologically increase pulmonary vascular resistance, leading to right ventricular failure and premature death. Nothing is known about the contribution of histone methylation to endothelial proliferation and neointima formation in PAH. We therefore aimed to evaluate the role of histone H3 trimethylation on lysine 27 (H3K27me3) on pulmonary vascular endothelial cell proliferation, apoptosis and inflammatory response. Methods and Results: Immunofluorescent staining was used to localize expression of H3K27me3 and JMJD3, which demethylates H3K27me3, in pulmonary arterial lesions of idiopathic PAH. The effect of the selective JMJD3 inhibitor GSK-J4 was assessed in cultured primary pulmonary microvascular endothelial cells. GSK-J4 significantly decreased BrdU incorporation resulting in decreased proliferation (p Conclusion: These data demonstrate a novel role of H3K27me3 and its demethylase JMJD3 as regulators of pulmonary vascular endothelial cell activation in PAH.