Abstract

Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and remodeling that result in right heart failure. Recessive mutations of EIF2AK4 gene (encoding GCN2, General control nonderepressibe 2 kinase) are linked to heritable pulmonary veno-occlusive disease (PVOD) in patients but rarely (approximately one percent) in PAH patients. The role of GCN2 kinase activation in the pathogenesis of PAH remains unclear. Here we show that GCN2 was hyperphosphorylated and activated in pulmonary vascular endothelial cells (ECs) of hypoxic mice, monocrotaline-treated rats, and PAH patients. Unexpectedly, loss of GCN2 kinase activity in Eif2ak4-/- mice with genetic disruption of the kinase domain induced neither PVOD nor PH but inhibited hypoxia-induced PH. RNA sequencing analysis suggested Endothelin-1 (Edn1) as a downstream target of GCN2. GCN2 mediated hypoxia-induced Edn1 expression in human lung ECs via HIF-2α. Restored Edn1 expression in ECs of Eif2ak4-/- mice partially reversed the reduced phenotype of hypoxia-induced PH. Furthermore, GCN2 kinase inhibitor A-92 treatment attenuated PAH in monocrotaline-treated rats. These studies demonstrate that GCN2 kinase activation mediates pulmonary vascular remodeling and PAH at least partially through Edn1. Thus, targeting GCN2 kinase activation is a promising therapeutic strategy for treatment of PAH in patients without EIF2AK4 loss of function mutations.