The Role of Glutamine and Glutaminase in Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) refers to a clinical and pathophysiological syndrome in which pulmonary vascular resistance and pulmonary arterial pressure are increased due to structural or functional changes in pulmonary vasculature caused by a variety of etiologies and different pathogenic mechanisms. It is followed by the development of right heart failure and even death. In recent years, most studies have found that PH and cancer shared a complex common pathological metabolic disturbance, such as the shift from oxidative phosphorylation to glycolysis. During the shifting process, there is an upregulation of glutamine decomposition driven by glutaminase. However, the relationship between PH and glutamine hydrolysis, especially by glutaminase is yet unclear. This review aims to explore the special linking among glutamine hydrolysis, glutaminase and PH, so as to provide theoretical basis for clinical precision treatment in PH.

Keywords: glutaminase; glutamine hydrolysis; pulmonary hypertension; targeted therapy; tricarboxylic acid cycle.

FIGURE 1

Overview of glutamine metabolism in pulmonary arterial hypertension. Under pathological stress or upon activation of oncogenes, glutamine (Gln) is transported from extracellular to intracellular space by alanine-serine-cysteine transporter 2 (ASCT2) [also known as solute carrier family 1, member 5 (SLC1A5)]. Gln is then hydrolyzed to glutamate (GLU) and ammonia (NH3) driven by increased GLS expression in mitochondria. GLU is transformed into α-ketoglutaric acid (α-KG), which participates in the tricarboxylic acid (TCA) cycle for energy supply. During the process, the abnormal glutamine metabolism would ultimately lead to the pathological changes of pulmonary arterial hypertension via modulation of redox homeostasis, cell proliferation, autophagy and synthesis of biological macromolecules. Myc, MYC proto-oncogene; KRAS, kirsten rat sarcoma viral oncogene; p53, p53 gene; GLUD, glutamate dehydrogenase; ISO, isocitrate; Cit, citrate; OAA, oxaloacetate; Mal, malate; Fum, fumarase; Suc, succinic acid; Asn, asparagine; Asp, aspartate; ASL, argininosuccinate lyase; NO, nitric oxide; Pyr, pyruvate; NADPH, nicotinamide adenine dinucleotide phosphate; NADP, nicotinamide adenine dinucleotide phosphate.