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A4613 - Receptor for Advanced Glycation End Products (RAGE) Regulates Metabolic Reprogramming Induced Over-Proliferation in Pulmonary Hypertension
Author Block: O. Rafikova, M. L. McBride, P. R. Langlais, R. Rafikov; Medicine, University of Arizona, Tucson, AZ, United States.
Introduction: Pulmonary arterial hypertension (PAH) is a deadly disease with limited therapeutic options. The uncontrolled cancer-like proliferation of pulmonary vascular cells is a primary characteristic of PAH, although the molecular mechanisms responsible for this proliferative phenotype are not fully understood. RAGE activated by damage-associated molecular patterns (DAMPs) is known to be involved in mediating the pro-survival signaling.
Hypothesis: We hypothesized that RAGE plays an important role in the transition of initially damaged pulmonary vascular cells to the cells possessing an over-proliferative phenotype.
Methods: To induce pulmonary hypertension (PH), female SD rats were injected with 50mg/kg of SU5416 and exposed to 3 weeks of hypoxia (10% of oxygen) followed by 2 weeks of normoxia. RAGE was immunoprecipitated from lungs and analyzed for protein interactome using immunoblotting and mass spectrometry.
Results: This severe model of PH induced an early (week 1) and late (week 5) apoptosis in lungs and an increased interaction of RAGE with HMGB1. PH has also initiated a formation of a novel complex of RAGE with inositol monophosphatase 1 (IMPA1). IMPA1 is an enzyme that protects cells from an osmotic stress induced by glucose metabolite, glucose-6-phosphate (G6P), through its conversion to non-osmotic myo-inositol. Indeed, we found that PH induced an activation of glucose transport and metabolism in lungs, as glucose transporters, GLUT1 and GLUT4, were accumulated on a plasma membrane and the levels of pulmonary G6P were strongly enhanced. Activation of IMPA1-induced inositol metabolism stimulated the inositol-sensitive pathways. Thus, we found that membrane translocation of phosphoinositol-3 kinase (PI3K) catalytic subunits p110α and p110γ and accumulation of phosphatidylinositol (3,4,5)-triphosphate (PIP3) were upregulated in rats with PH. These changes in inositol synthesis have correlated with a pronounced membrane translocation and activation of a PI3K-dependent proliferative factor, Akt, and severe remodeling of small and larger pulmonary arteries. Finally, the treatment with anti-RAGE peptide, which prevents binding of DAMPs to RAGE, has attenuated right ventricle (RV) systolic pressure (58.8±7.6 vs. 113±6 mmHg) and RV hypertrophy (1.2±0.14 vs. 2.0±0.2 mg/g), suggesting an important role of RAGE in PH.
Conclusions: This is a very first evidence of the new role of RAGE to mediate the glycolytic shift induced activation of proliferative pathways through the formation of a complex with IMPA1 and upregulation of inositol-mediated pathways.