Abstract 18437: Distinct Roles of Akt Isoforms in the Development of Hypoxia Induced Pulmonary Hypertension

Abstract

Rationale: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by persistent increase in pulmonary arterial pressure associated with vascular remodeling due to excessive pulmonary vascular cell proliferation and migration. Akt/mTOR signaling is involved in regulating cell growth, proliferation, migration and apoptosis. Akt is comprised of three isoforms, Akt1, Akt2, and Akt3, with distinct but overlapping functions. The aim of this study is to examine whether the Akt/mTOR pathway is activated in pulmonary arterial smooth muscle cells (PASMC) from patients with PAH and animals with experimental pulmonary hypertension (PH), and to examine whether Akt1 or Akt2 deficient mice are protected against hypoxia-mediated PH (HPH). Methods: Lung tissues from control subjects and PAH patients as well as control mice and mice with (HPH) were used to study changes in Akt/mTOR mRNA and protein levels using real-time PCR and Western blotting, respectively. WT, Akt1-/- and Akt2-/- mice were exposed to 10% oxygen for up to five weeks. Pulmonary vascular remodeling was evaluated using tissue morphometrics. Right ventricle systolic pressures (RVSP) and right ventricular hypertrophy by RV/(LV+S) ratios were measured to evaluate pulmonary hypertensive changes. Acute hypoxia-induced pulmonary vasoconstriction response, in both WT and KO mice, was evaluated by isolated perfused / ventilated mouse lung. Results: Phosphorylation of Akt and mTOR in lung tissues from PAH patients was significantly increased in comparison to the controls. Akt/mTOR signaling was upregulated in rat and mouse lungs with hypoxia-induced pulmonary hypertension. Akt1-/- mice had significantly lower RVSP, RV/LV+S ratios, and displayed less pulmonary vascular remodeling when compared to WT mice. AKT1-/- mice also had significantly lower pulmonary arterial pressure in response to acute pulmonary vasoconstriction challenges than their WT counterparts. Conclusion: These data indicate that Akt/mTOR signaling plays an important role in the development and progression of pulmonary vascular remodeling in patients and animals with PH. This study suggests a key role for Akt1 in vascular remodeling processes and provides a novel therapeutic target for treatment of PAH.