FIGURE 4.

Glutaminolysis in PAH. Above: In normal adult cells, glutaminolysis predominantly occurs in actively proliferating cells, like those of the gastrointestinal tract and kidneys. In pathologic states of hyperproliferation, as occurs in cancer cells, there is also marked upregulation of glutaminolysis. Cellular glutamine entry is enhanced through c-Myc/Max-mediated transcription of the glutamine transporter, LAT1 (SLC7A5), and the ASCT2 (SLC1A5). GLS then produces glutamate for entry into the Krebs cycle, leading to α-ketoglutarate synthesis and downstream production of fatty acids, purines, and other metabolites. Below: In PAH, increased glutaminolysis in the pulmonary vasculature increases vascular stiffness and obstruction. In the normal RV, there is little or no basal glutaminolysis; however in PAH, cMyc and Max dramatically upregulate glutaminolysis. This contributes to RV hypertrophy and reduces RV function. Abbreviations: ASCT2—Alanine-serine-cysteine transporter 2; GLS—Glutaminase; GDH—Glutamate dehydrogenase; LAT1—L-type amino acid transporter 1; RV—Right ventricle.