INOSITOL MONOPHOSPHATASE 1 (IMPA1) AS A NOVEL INTERACTING PARTNER OF RAGE IN PULMONARY HYPERTENSION.

Pulmonary arterial hypertension (PAH) is a lethal disease characterized by progressive pulmonary vascular remodeling. The receptor for advanced glycation endproducts (RAGE) plays an important role in PAH by promoting proliferation of pulmonary vascular cells. RAGE is also known to mediate activation of Akt signaling, although the particular molecular mechanism remains unknown. This study aimed to identify the interacting partner of RAGE that could facilitate RAGE-mediated Akt activation and vascular remodeling in PAH. The progressive angioproliferative PAH was induced in 24 female Sprague-Dawley rats (n=8/group) that were randomly assigned to develop PAH for one, two or five weeks (right ventricle peak systolic pressure (RVPSP) 56.5±3.2mmHg, 63.6±1.6mmHg and 111.1±4.5mmHg respectively vs. 22.9±1.1mmHg in Controls). PAH triggered early and late episodes of apoptosis in rat lungs accompanied by RAGE activation. Mass spectrometry analysis has identified IMPA1 as a novel PAH-specific interacting partner of RAGE. The proximity ligation assay (PLA) confirmed the formation of RAGE/IMPA1 complex in the pulmonary artery wall. Activation of IMPA1 in response to increased glucose-6-phosphate (G6P) is known to play a critical role in inositol synthesis and recycling. Indeed, we confirmed a 3-fold increase of G6P (p=0.0005) levels in lungs of PAH rats starting from week 1 that correlated with accumulation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), membrane translocation of PI3K, and a 3-fold increase in membrane Akt levels (p=0.02) and Akt phosphorylation. We conclude that the formation of the newly discovered RAGE/IMPA1 complex could be responsible for the stimulation of inositol pathways and activation of Akt signaling in PAH.