Fig. 10.

Schematic representation of the proposed protein kinase B (Akt) activation in response to receptor for advanced glycation end products (RAGE)-inositol monophosphatase 1 (IMPA1) interaction. Accumulation of glucose (G) transporter type 4 (GLUT4) on a plasma membrane at the early stage of pulmonary arterial hypertension (PAH) increases glucose uptake and formation of glucose 6-phosphate (G6P). The increased levels of G6P stimulate IMPA1 activation and membrane translocation. Simultaneous activation of RAGE occurs in response to its interaction with damage-associated molecular patterns (DAMPs) that are released from dying cells. The formation of the RAGE-IMPA1 complex on a plasma membrane accelerates inositol synthesis and recycling. Phosphatidylinositol-3-kinase (PI3K) converts phosphatidylinositol 4,5-bisphosphate (PIP₂) into phosphatidylinositol (3,4,5)-trisphosphate (PIP₃), which mediates Akt membrane translocation and activation. The active Akt not only stimulates activation of proliferative pathways but also ensures GLUT4 translocation on a plasma membrane, thus maintaining the feedforward stimulation of proliferative mechanisms. Thus, we propose that the co-occurrence of the early vascular damage and the glycolytic shift could be responsible for the persistent activation of uncontrolled growth in pulmonary vascular cells. Ins, inositol; IP, inositol monophosphate; IP₃, inositol 1,4,5-trisphosphate; p85, regulatory subunit of phosphatidylinositol-4,5-bisphosphate 3-kinase; p100, catalytic subunit of PIP3K; pS473, phosphorylated Ser⁴⁷³ of Akt.