Pentose Phosphate Pathway controls endothelial-to-mesenchymal transition

Pentose phosphate pathway is a metabolic pathway parallel to glycolysis that has two main products: NADPH, that provides the reducing power for numerous anabolic reactions, and the ribose-5-phosphate, a precursor required for nucleotides synthesis. This metabolic pathway consists of an oxidative (oxPPP) and a nonoxidative phase (non-oxPPP). The oxidative phase involves a series of two irreversible reactions that are catalysed by G6PD (Glucose-6-phosphate dehydrogenase) and PGD (phosphogluconate dehydrogenase), respectively. Endothelial-to-mesenchymal-transition (EndoMT) is a cellular process characterized by the loss of endothelial features and the acquisition of mesenchymal phenotype. EndoMT is physiological for cardiac development, but it can also be linked to a wide range of pathological conditions such as atherosclerosis, organ fibrosis and pulmonary hypertension. This transformation is connected to the endothelial metabolism and therefore a therapeutic manipulation of their metabolism could be a possible treatment for these pathological conditions. Thanks to preliminary data from the lab, it has been shown that a deregulation of the PPP pathway is linked to an increase of inflammation and EndoMT; hence, the thesis project is aimed to study the role of oxPPP pathway in controlling/modulating EndoMT. To evaluate the contribution of oxPPP in several pathological conditions, we will characterize the EndoMT signature in cultured endothelial cells under oxPPP silencing using shRNA for G6PD and PGD or inhibiting the G6PD activity using 6-aminonicotinamide (6-AN). What we expect is to be able to appreciate in vitro the transition from endothelial to mesenchymal features by western blot and qPCR, supporting a novel function of this metabolic pathway in EndoMT.