Akt1 Nitration Promotes Proliferation and Mesenchymal Transition Exacerbating Pulmonary Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vascular remodeling and increased pulmonary arterial resistance. This study investigates the role of Akt1 nitration in PAH development, focusing on its effect on endothelial-to-mesenchymal transition (EndMT) and vascular cell proliferation. Using the novel Akt1Y350F mutant mouse model, which resists nitration due to a tyrosine-to-phenylalanine substitution, we demonstrated that Akt1 nitration is a key pathogenic factor in PAH progression. Our results show that Akt1Y350F mice, resistant to Akt1 nitration, are protected against PAH in a SU5416/hypoxia (SU5416/Hx) model, exhibiting lower right ventricular systolic pressure (RVSP), reduced right ventricular hypertrophy, and decreased vascular occlusion. Additionally, we identified important molecular mechanisms involving TWIST1, SMA, HIF1, and STAT3 signaling pathways that influence EndMT and vascular remodeling. The proteomic analysis revealed other affected pathways, including angiogenesis, lipid metabolism, and mitochondrial function. We demonstrate that oxidative and nitrative stress-induced post-translational modifications contribute to the pathological processes leading to pulmonary hypertension, using a unique Akt nitration-resistant mouse model. These findings provide new insights into the molecular mechanisms underlying PAH and suggest that targeting Akt1 nitration could be a promising therapeutic approach for this devastating disease.